• C3 glomerulopathy
• autoantibody
• complement
• genetic
• glomerulopathy

• Humans
• Complement C3/metabolism
• Complement C3/genetics
• Complement C3/immunology
• Phenotype
• Glomerulonephritis, Membranoproliferative/genetics
• Glomerulonephritis, Membranoproliferative/therapy
• Glomerulonephritis, Membranoproliferative/pathology
• Glomerulonephritis, Membranoproliferative/etiology
• Glomerulonephritis, Membranoproliferative/immunology
• Prognosis
• Immunoglobulins
• Complement Activation

• ANR-20-CE17 ANR

• 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

• Humans
• Complement C3/metabolism
• Complement C3/immunology
• Glomerulonephritis, Membranoproliferative/therapy
• Glomerulonephritis, Membranoproliferative/immunology
• Glomerulonephritis, Membranoproliferative/diagnosis
• Glomerulonephritis, Membranoproliferative/drug therapy
• Glomerulonephritis, Membranoproliferative/pathology
• Antibodies, Monoclonal, Humanized/therapeutic use
• Complement Pathway, Alternative/drug effects
• Complement Pathway, Alternative/immunology
• Glomerulonephritis/therapy
• Glomerulonephritis/diagnosis
• Glomerulonephritis/immunology
• Glomerulonephritis/physiopathology
• Glomerulonephritis/drug therapy
• Complement Inactivating Agents/therapeutic use
• Complement Inactivating Agents/pharmacology

• C3 glomerulopathy
• case series
• complement
• disease recurrence
• kidney transplantation

• Humans
• Complement C3/metabolism
• Complement Activation
• Glomerulonephritis/immunology
• Kidney/immunology
• Kidney/pathology
• Kidney Glomerulus/immunology
• Kidney Glomerulus/pathology

• ANR-20-CE17, COMSIGN ANR
• 2019 Kidneeds
• 2022 Kidneeds
• 2022 ORKID
• 2023 SFNDT

• Alternative pathway of complement
• Avacopan
• C3 glomerulopathy
• C5a complement receptor inhibitor
• Child
• Membranoproliferative glomerulonephritis

• Child
• Female
• Humans
• Complement C3
• Glomerulonephritis/drug therapy
• Glomerulonephritis, Membranoproliferative/pathology
• Treatment Outcome
• Randomized Controlled Trials as Topic

• complement system
• diabetic kidney disease
• inflammation

• C3 glomerulonephritis
• C3 glomerulopathy
• Complement
• Dense deposit disease
• Eculizumab

Metabolic syndrome (MS) is a group of clinical abnormalities characterized by central or abdominal obesity, hypertension, hyperuricemia, and metabolic disorders of glucose or lipid. Currently, the prevalence of MS is estimated about 25% in general population and is progressively increasing, which has become a challenging public health burden. Long-term metabolic disorders can activate the immune system and trigger a low-grade chronic inflammation named “metaflammation.” As an important organ involved in metabolism, the kidney is inevitably attacked by immunity disequilibrium and “metaflammation.” Recently, accumulating studies have suggested that the complement system, the most important and fundamental component of innate immune responses, is actively involved in the development of metabolic kidney diseases. In this review, we updated and summarized the different pathways through which the complement system is activated in a series of metabolic disturbances and the mechanisms on how complement mediate immune cell activation and infiltration, renal parenchymal cell damage, and the deterioration of renal function provide potential new biomarkers and therapeutic options for metabolic kidney diseases.

• Complement System Proteins/metabolism
• Humans
• Kidney Diseases/complications
• Metabolic Diseases/metabolism
• Metabolic Syndrome
• Obesity/complications

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

• Antibodies, Antineutrophil Cytoplasmic/analysis
• Antibodies, Antineutrophil Cytoplasmic/therapeutic use
• Biopsy/adverse effects
• Female
• Glomerulonephritis/pathology
• Glomerulonephritis, IGA
• Hematuria/etiology
• Humans
• Male
• Proteinuria/complications

• C3 glomerulopathy
• Children
• Complement
• Glomerular disease

• Alternative complement pathway
• C3 glomerulopathy
• C3/C5 convertase
• Complement
• Inhibition

Complement factor H (FH) is a key regulator of the alternative pathway of complement, in man and mouse. Earlier, our studies revealed that the absence of FH causes the C57BL6 mouse to become susceptible to chronic serum sickness (CSS) along with an increase in the renal infiltration of macrophages compared to controls. To understand if the increased recruitment of macrophages (Mϕs) to the kidney was driving inflammation and propagating injury, we examined the effect of Mϕ depletion with clodronate in FH knockout mice with CSS. Eight-week-old FHKO mice were treated with apoferritin (4 mg/mouse) for 5 wks and with either vehicle (PBS) or clodronate (50 mg/kg ip, 3 times/wk for the last 3 weeks). The administration of clodronate decreased monocytes and Mϕs in the kidneys by >80%. Kidney function assessed by BUN and albumin remained closer to normal on depletion of Mϕs. Clodronate treatment prevented the alteration in cytokines, TNFα and IL-6, and increase in gene expression of connective tissue growth factor (CTGF), TGFβ-1, matrix metalloproteinase-9 (MMP9), fibronectin, laminin, and collagen in FHKO mice with CSS (P < 0.05). Clodronate treatment led to relative protection from immune complex- (IC-) mediated disease pathology during CSS as assessed by the significantly reduced glomerular pathology (GN) and extracellular matrix. Our results suggest that complement activation is one of the mechanism that regulates the macrophage landscape and thereby fibrosis. The exact mechanism remains to be deciphered. In brief, our data shows that Mϕs play a critical role in FH-dependent ICGN and Mϕ depletion reduces disease progression.

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

• Avacopan
• C3
• C5
• Complement inhibitors
• Complement system
• Complosome
• Eculizumab
• Immunology
• Kidney disease

• Animals
• Complement Activation
• Complement System Proteins
• Humans
• Immunity, Innate
• Kidney Diseases/therapy

• ZIA DK075149 Intramural NIH HHS

• Atypical hemolytic uremic syndrome
• Eculizumab
• Hemolytic uremic syndrome
• Pediatric

• graft survival
• kidney disease
• regeneration
• review
• transplantation

• C5b-9 (membrane attack complex [MAC])
• biopsy
• clinicopathological correlation
• glomerular disease
• histopathology
• immunofluorescence
• immunohistochemistry
• renal

• Complement Inactivating Agents/therapeutic use
• Complement Membrane Attack Complex/immunology
• Humans
• Kidney/immunology
• Kidney/pathology
• Kidney Diseases/drug therapy
• Kidney Diseases/immunology
• Kidney Diseases/pathology

• 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

Dense deposit disease (DDD), a subtype of complement component 3 (C3) glomerulopathy (C3G), results from alternative complement pathway hyperactivity leading to membrane attack complex formation. DDD treatment strategies are limited. We report a case of a 13-year-old girl diagnosed with DDD at 9 years of age, with nephritic and nephrotic syndrome and C3 nephritic factor-negative alternative complement pathway activation. Initial treatment with prednisolone, methylprednisolone pulses (MPs), and mizoribines was effective for 3 years, after which she relapsed. Despite MP treatment followed by prednisolone and mycophenolate mofetil (MMF), her kidney function and proteinuria deteriorated with a high soluble (s)C5b-9 level; she also developed dyspnea and pleural effusion (PE). Three days after the first eculizumab (ECZ) infusion, urine volume increased, respiratory condition improved, PE resolved, and proteinuria decreased in 1 month. Serum creatinine level decreased, and kidney function completely normalized within 7 weeks. The sC5b-9 level normalized, and although proteinuria decreased, nephrotic range proteinuria persisted during ECZ treatment with MMF for 53 weeks, even with increased treatment interval. Thus, complement activation pathway-targeted therapy may be useful for rapidly progressing DDD. Our data support the role of complement pathway abnormalities in C3G with DDD.

• C3 glomerulopathy
• C5b-9
• alternative complement pathway
• dense deposit disease
• eculizumab

The reclassification of membranoproliferative glomerulonephritis (MPGN) into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G) has provided insights into 2 distinct diseases. Although outcomes in adults are poor in both diseases, the pediatric literature is scarce and limited to small, single-center cohorts.

We conducted a retrospective analysis of 165 pediatric patients across 17 hospitals to compare outcomes between children with IC-MPGN and C3G.

Forty-two percent of patients initially diagnosed with MPGN were reclassified as C3G after a review of renal biopsy reports. There was a trend toward higher serum creatinine levels in patients with C3G compared with IC-MPGN both at diagnosis (mean 168.9 [range 45.4–292.4] vs. 93.7 [range 70.7–116.6] μmol/l, P = 0.25) and after a mean follow-up time of 4 years (mean 145.0 (range −8.1 to 298.1) vs 99.1 (range 46.3–151.9) μmol/l, P = 0.47), although the estimated glomerular filtration rate (eGFR) was not significantly different. Steroid treatment was associated with a significant improvement in eGFR versus no steroids in C3G (mean +43.0 (range 12.9–73.0) vs. −3.0 (range −23.1 to 17.2) ml/min per 1.73 m², P = 0.02) but not in IC-MPGN. Overall kidney function was preserved in both groups although hypertension remained prevalent in 42.5% of the cohort at the last follow-up, and the urine protein/creatinine ratio remained elevated (mean 253.8 [range 91.9–415.7] mg/mmol).

This large pediatric IC-MPGN/C3G cohort revealed nearly half of the patients were misclassified, and there may be a trend toward worse renal prognosis in C3G although they may have greater steroid responsiveness. The overall prognosis appears to be more favorable than in adults; however, persistent hypertension and proteinuria suggest suboptimal disease control.

• C3 glomerulonephritis
• C3 glomerulopathy
• dense deposit disease
• hypertension
• immune-complex membranoproliferative glomerulonephritis
• proteinuria

• C3 glomerulonephritis
• C3 glomerulopathy
• dense deposit disease
• kidney transplantation
• renal transplantation

Eculizumab is the first drug approved for the treatment of complement-mediated diseases, and current dosage schedules result in large interindividual drug concentrations. This review provides insight into the pharmacokinetic and pharmacodynamic properties of eculizumab, both for reported on-label (paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis) and off-label (hematopoietic stem cell transplantation-associated thrombotic microangiopathy) indications. Furthermore, we discuss the potential of therapeutic drug monitoring to individualize treatment and reduce costs.

There is no evidence-based definition for diagnosing crescentic glomerulonephritis. The prognostic implications of crescentic lesions on kidney biopsy have not been quantified. Our objective was to determine risk factors for end-stage kidney disease (ESKD) in patients with glomerulonephritis and crescents on kidney biopsy. A query of the Pediatric Nephrology Research Consortium’s Pediatric Glomerulonephritis with Crescents registry identified 305 patients from 15 centers. A retrospective cohort study was performed with ESKD as the primary outcome. Median age at biopsy was 11 years (range 1–21). The percentage of crescents was 3–100% (median 20%). Etiologies included IgA nephropathy (23%), lupus (21%), IgA vasculitis (19%) and ANCA-associated GN (13%), post-infectious GN (5%), and anti-glomerular basement membrane disease (3%). The prevalence of ESKD was 12% at one year and 16% at last follow-up (median = 3 years, range 1–11). Median time to ESKD was 100 days. Risk factors for ESKD included %crescents, presence of fibrous crescents, estimated GFR, and hypertension at biopsy. For each 1% increase in %crescents, there was a 3% decrease in log odds of 1-year renal survival (p = 0.003) and a 2% decrease in log odds of renal survival at last follow-up (p < 0.001). These findings provide an evidence base for enrollment criteria for crescentic glomerulonephritis in future clinical trials.

• cellular crescents
• fibrous crescents
• glomerulonephritis
• immunosuppression
• targeted biologic therapies

• children
• complement cascade
• histology
• pathophysiology
• primary glomerulonephritis
• review
• treatment

• Chronic kidney disease
• Complement
• Glomerular diseases
• Renal fibrosis

• Clinical trial
• Complement
• Disease
• Drug
• Eculizumab
• Therapeutic

• C3 glomerulopathy
• children
• outcome
• treatment

• 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

• Clinical trial
• Complement
• Drug
• Eculizumab
• Indication
• Therapeutic

• Activación del complemento
• Complement activation
• Eculizumab
• Microangiopatías trombóticas secundarias
• Secondary thrombotic microangiopathies

• Antibodies, Monoclonal, Humanized/pharmacology
• Antibodies, Monoclonal, Humanized/therapeutic use
• Antineoplastic Agents/adverse effects
• Autoimmune Diseases/complications
• Complement Activation/drug effects
• Complement C5/antagonists & inhibitors
• Female
• Glomerulonephritis/complications
• Humans
• Organ Transplantation
• Postoperative Complications/drug therapy
• Postoperative Complications/immunology
• Postoperative Complications/physiopathology
• Pregnancy
• Pregnancy Complications/drug therapy
• Pregnancy Complications/immunology
• Pregnancy Complications/physiopathology
• Thrombotic Microangiopathies/drug therapy
• Thrombotic Microangiopathies/etiology
• Thrombotic Microangiopathies/immunology
• Thrombotic Microangiopathies/physiopathology

• complement
• glomerulopathy
• membranoproliferative glomerulonephritis (MPGN)

Monoclonal gammopathy causes several kinds of renal pathology. A rare and special form is monoclonal gammopathy-induced C3 glomerulopathy (MG-C3G). Like idiopathic C3G, MG-C3G frequently leads to end-stage renal disease. MG-C3G frequently recurs after renal transplantation, leading to graft failure in most of the patients. While there is some evidence for successful treatment of recurrent idiopathic C3 glomerulopathy with eculizumab after renal transplantation, nothing is known about its efficacy in the setting of recurrent MG-C3G.

We report a patient with recurrent MG-C3G in a renal allograft that was successfully treated with eculizumab in addition to standard immunosuppression. He had early recurrence of MG-C3G 2 months after transplantation. His graft function successively declined despite high dose steroids and plasmapheresis. Only after therapy with three cycles of bortezomib and continuous therapy with eculizumab, his graft function stabilized. He was still in clinical remission after 28 months of follow-up without having experienced major infectious complications.

Eculizumab may be a safe and effective treatment of recurrent MG-C3G. Because of the high and early recurrence risk, renal transplantation should be reviewed carefully for every individual patient. Subsequent hematopoietic stem cell transplantation may ameliorate long-term renal allograft survival. Eculizumab might serve as a bridging therapy until stem cell transplantation.

• Acquired complement disorders
• Eculizumab
• Monoclonal gammopathy
• Renal transplantation

• C3 glomerulopathies
• Digital ischemia
• Eculizumab
• Factor H antibody

• Aged
• Antibodies, Monoclonal, Humanized/therapeutic use
• Autoantibodies
• Complement C3/immunology
• Complement Factor H/immunology
• Female
• Glomerulonephritis/drug therapy
• Glomerulonephritis/immunology
• Humans
• Ischemia/drug therapy
• Ischemia/immunology

• Complement Membrane Attack Complex
• Follow-Up Studies
• Humans
• Immunosuppressive Agents
• Mycophenolic Acid
• Recurrence
• Registries
• Retrospective Studies
• Universities
• complement
• creatinine
• glomerular disease
• glomerulonephritis
• immunosuppression
• mycophenolate mofetil
• proteinuria

• Adolescent
• Adult
• Anti-Inflammatory Agents/therapeutic use
• Complement C3/genetics
• Complement C3/immunology
• Complement C3/metabolism
• Creatinine/blood
• Drug Therapy, Combination
• Female
• Glomerulonephritis, Membranoproliferative/drug therapy
• Glomerulonephritis, Membranoproliferative/etiology
• Humans
• Immunosuppressive Agents/therapeutic use
• Male
• Mycophenolic Acid/therapeutic use
• Prednisone/therapeutic use
• Proteinuria/etiology
• Retrospective Studies
• Treatment Outcome
• Exome Sequencing
• Young Adult

• R01 MD009223 NIMHD NIH HHS

• C3 glomerulopathy (C3G)
• C3 nephritic factor (C3Nef)
• anti-C5 monoclonal antibody
• case series
• clinical response
• complement
• eculizumab
• kidney biopsy
• membranoproliferative glomerulonephritis (MPGN)
• pediatric
• proteinuria
• rapidly progressive glomerulonephritis

The advances in our understanding of the alternative pathway have emphasized that uncontrolled hyperactivity of this pathway causes 2 distinct disorders that adversely impact the kidney. In the so-called atypical hemolytic uremic syndrome (aHUS), renal dysfunction occurs along with thrombocytopenia, anemia, and target organ injury to multiple organs, most commonly the kidney. On the other hand, in the so-termed C3 glomerulopathy, kidney involvement is not associated with thrombocytopenia, anemia, or other system involvement. In this report, we present 2 cases of alternative pathway dysfunction. The 60-year-old female patient had biopsy-proven C3 glomerulopathy, while the 32-year-old female patient was diagnosed with aHUS based on renal dysfunction, thrombocytopenia, anemia, and normal ADAMTS-13 level. The aHUS patient was successfully treated with the monoclonal antibody (eculizumab) for complement blockade. The patient with C3 glomerulopathy did not receive the monoclonal antibody. In this patient, management focused on blood pressure and proteinuria control with an angiotensin-converting enzyme inhibitor. This article focuses on the clinical differences, pathophysiology, and treatment of aHUS and C3 glomerulopathy.

• Atypical hemolytic uremic syndrome
• C3 glomerulopathy
• Complement dysfunction

C3 glomerulopathy (C3G) is a rare, but severe glomerular disease with grim prognosis. The complex pathogenesis is just unfolding, and involves acquired as well as inherited dysregulation of the alternative pathway of the complement cascade. Currently, there is no established therapy. Treatment with the C5 complement inhibitor eculizumab may be a therapeutic option. However, due to rarity of the disease, parameters predicting treatment response remain largely unknown.

Seven patients with C3G (five with C3 glomerulonephritis and two with dense deposit disease) were treated with eculizumab. Subjects underwent biopsy before enrollment. The histopathology, clinical data, and response to eculizumab treatment were analyzed. The key parameters to determine outcome were changes of serum creatinine and urinary protein over time.

After treatment with eculizumab, four subjects showed significantly improved or stable renal function and urinary protein. A positive response occurred between 2 weeks and 6 months after therapy initiation. One subject (with allograft recurrent C3 glomerulonephritis) initially showed a positive response, but relapsed when eculizumab was discontinued, and did not respond after re-initiation of treatment. Two subjects showed impaired renal function and increasing urinary protein despite therapy with eculizumab.

Eculizumab may be a therapeutic option for a subset of C3G patients. The response to eculizumab is heterogeneous, and early as well as continuous treatment may be necessary to prevent disease progression. These findings emphasize the need for studies identifying genetic and functional complement abnormalities that may help to guide eculizumab treatment and predict response.

The online version of this article (10.1186/s12882-017-0802-4) contains supplementary material, which is available to authorized users.

• C3 glomerulonephritis
• C3 glomerulopathy
• Complement
• Dense deposit disease
• Eculizumab