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Fergus LO, Waldmann M, Hall MD, Vining L, Hall J, Liu T, Zhang Y, Walker PJ, Smith RJH, Nester CM. Pregnancy outcomes in C3 glomerulopathy: a retrospective review. BMC Nephrol 2025; 26:238. [PMID: 40369503 PMCID: PMC12080063 DOI: 10.1186/s12882-025-04118-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 04/11/2025] [Indexed: 05/16/2025] Open
Abstract
BACKGROUND C3 Glomerulopathy (C3G) is an ultra-rare glomerular disease driven by dysregulation of the alternative pathway of complement. 30-50% of adult patients progress to end stage kidney disease (ESKD) within 10 years of diagnosis. Little is known of the impact of pregnancy on the natural history of C3G or whether a coincident diagnosis of C3G affects maternal-fetal outcomes. METHODS Female subjects from the University of Iowa's C3G Natural History Study who met consensus biopsy criteria were included if they had at least one pregnancy and available renal/obstetric data. Assessed data included clinical history, kidney function tests, and complement tests to identify genetic and/or acquired drivers of complement dysregulation. Appropriate t-tests or z-tests were used to compare outcomes and clinical biomarker changes pre-/post-pregnancy. Nonlinear regression and relative risk were used to estimate risk for preeclampsia, premature delivery, and progression to ESKD. RESULTS Amongst mothers whose C3G presented before or during pregnancy (C3G + P), there were 37 pregnancies and 27 deliveries. Non-live birth outcomes impacted 10 C3G + P and included 5 spontaneous miscarriages, 1 stillbirth, 1 ectopic pregnancy, and 3 elective abortions. Twelve deliveries (44%) were premature, while 16 (59%) were associated with antepartum preeclampsia: an elevated risk when compared to healthy pregnancies and pregnancies of mothers with other glomerular diseases. Risk factors for complications included preexisting hypertension, an identified driver of complement dysregulation, and an eGFR prior to pregnancy of < 60 ml/min/1.73m2. These risk factors also predict progression to ESKD within 5 (5/32, 16%) and 10 years (6/32, 19%) following pregnancy. Compared to pre-pregnancy values, post-pregnancy serum creatinine levels trended upwards and eGFRs downwards, both by small but significant amounts. Individual pre-/post-pregnancy eGFRs were significantly worse in mothers who progressed to ESKD within 5-10 years of pregnancy. CONCLUSIONS A C3G + P is associated with increased risk of preeclampsia and prematurity compared to healthy controls, but no excess risk of spontaneous miscarriage. A C3G + P was associated with a small but significant decrease in renal function as measured by change in creatinine and eGFR. The elevated risk of adverse renal and obstetric events supports the need for multidisciplinary care for expectant patients with C3G.
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Affiliation(s)
- Lauren O Fergus
- University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, IA, USA.
| | - Meryl Waldmann
- Kidney Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Monica D Hall
- University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, IA, USA
| | - Lynn Vining
- University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, IA, USA
| | - Jillian Hall
- University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, IA, USA
| | - Tina Liu
- University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, IA, USA
| | - Yuzhou Zhang
- University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, IA, USA
| | | | - Richard J H Smith
- University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, IA, USA
- University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Carla M Nester
- University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, IA, USA
- University of Iowa Hospitals and Clinics, Iowa City, IA, USA
- Stead Family Children's Hospital, Iowa City, IA, USA
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2
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Attieh RM, Bharati J, Sharma P, Nair G, Ayehu G, Jhaveri KD. Kidney transplant in patients with C3 glomerulopathy. Clin Kidney J 2025; 18:sfaf134. [PMID: 40385590 PMCID: PMC12082085 DOI: 10.1093/ckj/sfaf134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2025] [Indexed: 05/20/2025] Open
Abstract
Complement protein 3 (C3) glomerulopathy (C3G) is a rare and progressive kidney disease primarily affecting young individuals and frequently advancing to end-stage kidney disease (ESKD). For ESKD, kidney transplantation remains the optimal treatment option; however, C3G has a high recurrence rate post-transplantation, affecting over two-thirds of transplanted patients. Despite advances in our understanding of C3G, significant gaps persist regarding the optimal timing for transplantation and the best strategies for peri-transplant management. Currently, no clear evidence links functional complement levels to the risk of post-transplant recurrence. Genetic counseling is also complex, due to variable gene penetrance and weak genotype-phenotype correlations, which limit predictive accuracy. Transplant-related factors are believed to significantly influence C3G recurrence, yet there are no established methods for preventing recurrence after transplantation. Eculizumab has shown inconsistent efficacy in managing recurrent C3G. However, new proximal complement inhibitors, such as factor B and C3 inhibitors, are under investigation in clinical trials and show promise. Some of these trials include kidney transplant patients with C3G, and their outcomes could potentially shape future treatment protocols.
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Affiliation(s)
| | - Joyita Bharati
- Section of Nephrology, Boston Medical Center and Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Purva Sharma
- Division of Kidney Disease and Hypertension, Glomerular Center at Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
| | - Gayatri Nair
- Division of Kidney Disease and Hypertension, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
| | - Gashu Ayehu
- Division of Kidney Disease and Hypertension, Glomerular Center at Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
| | - Kenar D Jhaveri
- Division of Kidney Disease and Hypertension, Glomerular Center at Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY, USA
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Jalal DI, Thurman JM, Smith RJ. Chronic kidney disease enhances alternative pathway activity: a new paradigm. J Clin Invest 2025; 135:e188353. [PMID: 40309771 PMCID: PMC12043098 DOI: 10.1172/jci188353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025] Open
Abstract
Reduced kidney function is associated with increased risk of cardiovascular disease in addition to kidney disease progression. Kidney disease is considered an inflammatory state, based on elevated levels of C-reactive protein and inflammatory cytokines. A key mediator of cardiovascular and kidney disease progression in the setting of reduced kidney function is systemic and vascular inflammation. However, the exact pathways that link chronic kidney disease (CKD) with inflammation remain incompletely understood. For decades it has been known that factor D, the main activator of the alternative complement pathway, is increased in the plasma of patients with reduced kidney function. Recent biomarker evidence suggests alternative pathway activation in this setting. CKD, therefore, seems to alter the balance of alternative pathway proteins, promoting inflammation and potentially exacerbating complement-mediated diseases and CKD-associated complications. In this manuscript, we review the impact of reduced kidney function on biomarkers of the alternative complement pathway and the implications of alternative pathway activation on cardiovascular disease and kidney disease progression. Importantly, we highlight the need for ongoing research efforts that may lead to opportunities to target the alternative pathway of complement withx the goal of improving kidney and cardiovascular outcomes in persons with reduced kidney function.
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Affiliation(s)
- Diana I. Jalal
- Division of Nephrology, Department of Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
- Center for Access and Delivery Research and Evaluation, Iowa City VA Health Care System, Iowa City, Iowa, USA
| | - Joshua M. Thurman
- Division of Renal Diseases and Hypertension, Department of Medicine, Anschutz Medical Campus, University of Colorado, Aurora, Colorado, USA
| | - Richard J.H. Smith
- Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, Iowa, USA
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Meuleman MS, Roquigny J, Brousse R, El Sissy C, Durieux G, Quintrec ML, Van Huyen JPD, Frémeaux-Bacchi V, Chauvet S. Acquired and genetic determinants of disease phenotype and therapeutic strategies in C3 glomerulopathy and immunoglobulin-associated MPGN. Nephrol Dial Transplant 2025; 40:842-851. [PMID: 39537192 DOI: 10.1093/ndt/gfae245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Indexed: 11/16/2024] Open
Abstract
C3 glomerulopathy (C3G), a prototype of complement-mediated disease, is characterized by significant heterogeneity, in terms of not only clinical, histological and biological presentation but also prognosis, and response to existing therapies. Recent advancements in understanding the factors responsible for alternative pathway dysregulation in the disease have highlighted its even more complex nature. Here, we propose a reexamination of the diversity of C3G presentations in light of the drivers of complement activation. Autoantibodies targeting complement proteins, genetic abnormalities in complement genes and monoclonal immunoglobulins are now well-known to drive disease occurrence. This review discusses how these drivers contribute to the heterogeneity in disease phenotype and outcomes, providing insights into tailored diagnostic and therapeutic approaches. In recent years, a broad spectrum of complement inhibitory therapies has emerged, soon to be available in clinical practice. The recognition of specific clinical, biological and histological patterns associated with different forms of C3G is crucial for personalized management, particularly treatment strategies.
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Affiliation(s)
- Marie-Sophie Meuleman
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Inflammation, Complement and Cancer team, ILe de France, Paris, France
| | - Julia Roquigny
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Inflammation, Complement and Cancer team, ILe de France, Paris, France
- Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
| | - Romain Brousse
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Inflammation, Complement and Cancer team, ILe de France, Paris, France
| | - Carine El Sissy
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Inflammation, Complement and Cancer team, ILe de France, Paris, France
- Department of Immunology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), ILe de France, Paris, France
| | - Guillaume Durieux
- Department of Nephrology, European Hospital Georges Pompidou, APHP, Paris, France, CRMR MARHEA and ARMAC
| | - Moglie Le Quintrec
- Department of Nephrology, Montpellier University Hospital, Montpellier, France
| | - Jean-Paul Duong Van Huyen
- Department of Anathomopathology, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Ile de France, Paris, France
- Paris Cité University, Paris, France
| | - Véronique Frémeaux-Bacchi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Inflammation, Complement and Cancer team, ILe de France, Paris, France
- Department of Immunology, Georges Pompidou European Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), ILe de France, Paris, France
| | - Sophie Chauvet
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Inflammation, Complement and Cancer team, ILe de France, Paris, France
- Department of Nephrology, European Hospital Georges Pompidou, APHP, Paris, France, CRMR MARHEA and ARMAC
- Paris Cité University, Paris, France
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Cai W, Guo H, Zhang M, Liang H, Liang X, Wang Y, Shi Q, Ye Z, Li Z. Monoclonal gammopathy-associated C3 glomerulonephritis secondary to follicular lymphoma: a case report. Front Immunol 2025; 16:1551788. [PMID: 40342409 PMCID: PMC12058688 DOI: 10.3389/fimmu.2025.1551788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Accepted: 04/02/2025] [Indexed: 05/11/2025] Open
Abstract
C3 glomerulopathy encompasses a group of glomerular diseases characterized by the predominant deposition of complement component C3 on kidney biopsy without significant immunoglobulin staining. Monoclonal gammopathy (MIg)-associated C3 glomerulopathy is considered a distinct subtype. We report a case of a 38-year-old male with a history of HBV infection who presented with a left neck mass, hematuria, proteinuria, elevated creatinine, normal complement level, and an IgM kappa M-spike on serum immunofixation electrophoresis. He was diagnosed with follicular lymphoma-associated MIg-C3 glomerulonephritis (MIg-C3GN), accompanied by extensive infiltration of lymphoma cells in the renal interstitium. Kidney immunohistochemistry was positive for CD19 and CD20 (B-cell markers), as well as CD10 and Bcl2, confirming the follicular lymphoma subtype. Within the areas of lymphoma cell infiltration, immunohistochemistry was also positive for IgM and kappa light chains but negative for lambda light chains, consistent with the serum electrophoresis findings. Positive autoantibodies to complement C3 convertase and complement factor H indicated complement dysregulation. The patient successively underwent various chemotherapy and targeted therapy regimens. During nearly 2 years of follow-up, renal outcomes were favorable, with resolution of hematuria and proteinuria and normalization of renal function, suggesting that lymphoma-directed therapy can improve renal outcomes in MIg-C3GN. However, the patient achieved partial remission but later relapsed and progressed, with suspicion of transformation into diffuse large B-cell lymphoma.
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Affiliation(s)
- Wenjing Cai
- Department of Nephrology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Department of Nephrology, Heyuan People’s Hospital, Guangdong Provincial People’s Hospital Heyuan Hospital), Heyuan, Guangdong, China
| | - Hanguo Guo
- Department of Lymphoma, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Minghui Zhang
- Department of Pathology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Huaban Liang
- Department of Nephrology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Department of Nephrology, Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Guangzhou, Guangdong, China
| | - Xinling Liang
- Department of Nephrology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Department of Nephrology, Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Guangzhou, Guangdong, China
| | - Yihan Wang
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Qingying Shi
- Department of Nephrology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Zhiming Ye
- Department of Nephrology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Department of Nephrology, Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Guangzhou, Guangdong, China
| | - Zhilian Li
- Department of Nephrology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Department of Nephrology, Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Guangzhou, Guangdong, China
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Reddy S, Ghante A, Vankalakunti M, Vasudevan A. C3 glomerulopathy in children: experience at a resource-limited center. Clin Exp Pediatr 2025; 68:311-318. [PMID: 39608366 PMCID: PMC11969206 DOI: 10.3345/cep.2024.01256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 10/12/2024] [Accepted: 10/12/2024] [Indexed: 11/30/2024] Open
Abstract
BACKGROUND In children, C3 glomerulopathy (C3G) is a heterogeneous disease characterized by diverse clinicopathological profiles and kidney outcomes. However, diagnostic work-up in resource-limited settings is challenging because of the unavailability of complement assays and limited access to electron microscopy or genetic testing. PURPOSE This study aimed to describe the clinicopathological features and response to immunosuppression and evaluate renal outcomes among children with C3G in a resource-limited setting. METHODS This retrospective cohort study involved a review of the hospital records of 46 children (2013-2021) diagnosed with C3G on kidney biopsy. Their clinical, laboratory, treatment, and outcome details at onset and follow-up were noted. RESULTS The mean (standard deviation) age was 9 (4) years. The common presentation was acute nephritis (27 [58.6%]), while 1 in 5 (19.5%) presented with rapidly progressive glomerulonephritis. Focal crescentic glomerulonephritis (14 [30.4%]) was the common histological pattern. Electron microscopy was performed in 22 (47.8%), of which 17 were C3 glomerulonephritis and 4 were dense deposit disease (DDD). None of the patients underwent complement assay or genetic testing. Almost two-thirds (63%) received empirical immunosuppressive therapy, most commonly steroids. Of the 31/46 who completed follow-up (median [interquartile range] duration, 11.5 [6-24] months), 6 (19.4%) demonstrated complete kidney recovery, while the other 25 (80.7%) had kidney sequelae; of them, 5 (16.1%) progressed to end-stage kidney disease and 2 (4.3%) died by the last follow-up. CONCLUSION Pediatric C3G has a variable clinicopathological spectrum, while DDD is less common. Most patients present with glomerulonephritis and significant morbidities. The lack of genetic and C3Nephritic factor testing is a barrier to the comprehensive phenotyping and management of C3G in resource-limited settings.
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Affiliation(s)
- Soumya Reddy
- Department of Pediatric Nephrology, St. John's Medical College Hospital, St. John's National Academy of Health Sciences, Bengaluru, India
| | - Abhishek Ghante
- Department of Pediatric Nephrology, St. John's Medical College Hospital, St. John's National Academy of Health Sciences, Bengaluru, India
| | | | - Anil Vasudevan
- Department of Pediatric Nephrology, St. John's Medical College Hospital, St. John's National Academy of Health Sciences, Bengaluru, India
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Matola AT, Csuka D, Szilágyi Á, Rudnicki M, Prohászka Z, Józsi M, Uzonyi B. Autoantibodies Against Factor B and Factor H Without Pathogenic Effects in a Patient with Immune Complex-Mediated Membranoproliferative Glomerulonephritis. Biomedicines 2025; 13:648. [PMID: 40149624 PMCID: PMC11939916 DOI: 10.3390/biomedicines13030648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Revised: 02/24/2025] [Accepted: 02/27/2025] [Indexed: 03/29/2025] Open
Abstract
Background: Membranoproliferative glomerulonephritis (MPGN) is an umbrella term for chronic disorders affecting the glomeruli. MPGN is often accompanied by the presence of autoantibodies against complement components. However, the actual pathogenic effects of such autoantibodies, if any, are rarely studied. In this work, we investigated the role of anti-complement autoantibodies in an IC-MPGN patient. Methods: The presence of autoantibodies, their binding site, isotype, and titer were analyzed in ELISA. Antibody-antigen complexes were detected in the patient's serum using Western blot. Autoantibodies were studied in functional assays to analyze their effects on C3 convertase, complement deposition, cofactor activity, C3b binding, and hemolysis. Results: We identified autoantibodies against factor B (FB) and factor H (FH) in the patient's serum. Both FB-, and FH-autoantibodies were of IgG2, IgG3, IgG4, and IgGκ, IgGλ isotypes. FB-autoantibodies bound to the Ba and the enzymatically active Bb part of FB. FH-autoantibodies bound to the N- and C-termini of FH and cross-reacted with FHL-1 and FHR-1 proteins. In vivo formed complexes of the autoantibodies with both FB and FH were detected in the IgG fraction isolated from the serum. The autoantibodies did not influence solid-phase C3 convertase assembly and its FH-mediated decay. The free autoantibodies had no effect on complement deposition and on FH cofactor activity but slightly reduced C3b binding to FH. The IgG fraction of the patient dose-dependently inhibited complement-mediated rabbit red blood cell lysis, and the free autoantibodies decreased the solid phase C3 convertase activity. Conclusions: This case highlights that FB- and FH-autoantibodies are not necessarily pathogenic in IC-MPGN.
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Affiliation(s)
- Alexandra T. Matola
- Department of Immunology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, H-1117 Budapest, Hungary
| | - Dorottya Csuka
- Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
- HUN-REN-SE Research Group for Immunology and Hematology, Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
| | - Ágnes Szilágyi
- Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
- HUN-REN-SE Research Group for Immunology and Hematology, Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
| | - Michael Rudnicki
- Department of Internal Medicine IV, Medical University of Innsbruck, A-6020 Innsbruck, Austria
| | - Zoltán Prohászka
- Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
- HUN-REN-SE Research Group for Immunology and Hematology, Department of Internal Medicine and Hematology, Semmelweis University, H-1088 Budapest, Hungary
| | - Mihály Józsi
- Department of Immunology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, H-1117 Budapest, Hungary
| | - Barbara Uzonyi
- Department of Immunology, ELTE Eötvös Loránd University, H-1117 Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, H-1117 Budapest, Hungary
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Welsh SJ, Zhang Y, Smith RJH. Acquired drivers of C3 glomerulopathy. Clin Kidney J 2025; 18:sfaf022. [PMID: 40052168 PMCID: PMC11883229 DOI: 10.1093/ckj/sfaf022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Indexed: 03/09/2025] Open
Abstract
C3 glomerulopathy (C3G) is a group of heterogeneous ultrarare kidney diseases characterized by dysregulated activation of the complement alternative pathway (AP) leading to excessive C3 cleavage. Diagnosis relies on kidney biopsy showing predominant C3 deposition in the glomerular basement membrane, with electron microscopy differentiating between dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The main drivers of AP dysregulation in C3G are acquired rather than genetic and consist primarily of autoantibodies called nephritic factors (C3Nefs, C4Nefs and C5Nefs) that bind to and stabilize complement convertases, causing complement overactivation. Current therapies are largely supportive, and existing complement-targeting treatments, such as eculizumab, demonstrate limited efficacy. Challenges in studying C3G include variability in autoantibody detection and a lack of standardized assays, which complicates clinical interpretation. Comprehensive assessment involving autoantibody panels, complement biomarkers, functional assays and genetic testing provides a more complete understanding of disease dynamics; however, key knowledge gaps remain regarding Nef origins, mechanisms and their pathogenic role. In this review we discuss acquired drivers of C3G with an emphasis on C3Nefs and C5Nefs and suggest areas of interest that might benefit from future research.
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Affiliation(s)
- Seth J Welsh
- Department of Internal Medicine, Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Yuzhou Zhang
- Department of Internal Medicine, Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Richard J H Smith
- Department of Internal Medicine, Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
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9
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Duan ZY, Li JJ, Cai GY, Wang S, Tang X, Hou W, Jiang L, Song Y. C3 glomerulopathy associated with mycoplasma pneumoniae infection and positive IgA staining. BMC Nephrol 2025; 26:85. [PMID: 39966764 PMCID: PMC11837633 DOI: 10.1186/s12882-025-04010-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 02/05/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Patients with C3 glomerulopathy (C3G) often have a history of infection, which implies that infection may lead to abnormal activation of the complement alternative pathway (CAP) and induce the development of C3G. However, patients with postinfectious glomerulonephritis (PIGN) often have a low serum C3 concentration and positive glomerular C3 staining, consistent with the activation of the CAP. PIGN, especially if it involves simultaneous IgA deposition, is often difficult to differentiate from C3G. CASE PRESENTATION In this study, we report the consequences of Mycoplasma pneumoniae (MP) infection in a 66-year-old male Chinese patient, who developed persistent hypocomplementemia, gross hematuria, and rapidly progressive glomerulonephritis. The findings of the histologic examination of an initial renal biopsy were consistent with a diagnosis of IgA-dominant postinfectious glomerulonephritis. The sample was negative for Gd-IgA1 staining. After treatment with antibiotics, glucocorticoids, and mycophenolate mofetil, the patient's serum creatinine decreased from a peak of 387 µmol/L to 195 µmol/L prior to discharge, and there was a partial response in his urinary protein concentration. After 2 months, his serum C3 concentration had returned to normal. However, owing to reinfection with MP the patient's serum creatinine rapidly increased again to 475.07 µmol/L, and this was accompanied by a decrease in serum C3 concentration (> 8 months) and positivity for C3 nephritis factor. Examination of both renal biopsies showed stronger immunostaining for C3 than for IgA in the glomeruli. CONCLUSION Thus, MP infection can cause sustained activation of the CAP, leading to C3G. For patients with MP infection, if there is an ongoing decrease in complement C3 levels and a progressive increase in serum creatinine, it is crucial to be vigilant for possible C3G and to consider the use of immunosuppressive therapy in conjunction with anti-infective treatment to prevent the ongoing activation of the CAP.
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Affiliation(s)
- Zhi-Yu Duan
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, Beijing, 100853, China
| | - Ji-Jun Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, Beijing, 100853, China
| | - Guang-Yan Cai
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, Beijing, 100853, China
| | - SuXia Wang
- Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, 100034, China
| | - XuanLi Tang
- Department of Nephrology (Key Laboratory of Kidney Disease Prevention and Control Technology), Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310007, China
| | - WanYin Hou
- Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, 100034, China
| | - Lei Jiang
- Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, 100034, China
| | - Yan Song
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, Beijing, 100853, China.
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Roquigny J, Meuleman MS, el Sissy C, Cailliez M, Servais A, Roussey G, Baudouin V, Decramer S, Nobili F, Wynckel A, Sellier Leclerc AL, Lapeyraque AL, Martins PV, Meri S, Dragon-Durey MA, Chauvet S, Frémeaux-Bacchi V. Functional Characterization of Anti-C3bBb Autoantibodies and C3 Glomerulopathy Phenotype. J Am Soc Nephrol 2025; 36:264-273. [PMID: 39325562 PMCID: PMC11801764 DOI: 10.1681/asn.0000000000000499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 09/23/2024] [Indexed: 09/28/2024] Open
Abstract
Key Points Dysregulation of the C3bBb convertase is a key factor in the pathogenesis of C3 glomerulopathy and primary Ig-mediated membranoproliferative GN. IgG-driven increase of the C3bBb convertase formation was correlated with C3 consumption. IgG antibodies that promote the formation and the stabilization of the C3bBb convertase were associated with the severity of C3 glomerulopathy. Background C3 nephritic factors, that is, autoantibodies that stabilize the C3 convertase of the alternative pathway are the most frequent acquired abnormality in C3 glomerulopathy and primary Ig-mediated membranoproliferative GN (Ig-MPGN). Methods Our study included 27 patients with C3 glomerulopathy (n =21) or Ig-MPGN (n =6), of whom 78% were children at disease onset. At the time of sampling, 13/19 patients (68%) with low C3 levels and 8/8 patients (100%) with normal C3 levels were positive for C3 nephritic factors by hemolytic assay. Using novel Luminex assays, we performed a screening for IgG that recognize and affect the formation and/or the stabilization of the alternative pathway C3 convertase (C3bBb). Results Using Luminex assays, an increase in C3bBb formation and/or stabilization was observed in the presence of IgG from 18/27 patients, including nine with a double-function, six only enhancing the C3bBb formation, and three that exclusively stabilized C3bBb. All patients presenting a formation and stabilization function had a low C3 level versus 55% without this double-function. The level of C3bBb formation correlated to the plasmatic C3 but not soluble C5b-9 levels. The stabilization of C3bBb did not correlate with C3 or soluble C5b-9 levels. At the last follow-up, 5/27 patients (19%) reached kidney failure after a median delay of 87 (52–119) months. The patients positive for double-function anti-C3bBb antibodies had a 5-year kidney survival of 70% compared with 100% in those negative (P = 0.02). Conclusions Our findings highlight the association of the dual function of C3bBb formation and stabilization with severe C3 consumption and poor kidney survival in C3 glomerulopathy and Ig-MPGN.
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Affiliation(s)
- Julia Roquigny
- Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France
- Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
| | - Marie-Sophie Meuleman
- Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France
| | - Carine el Sissy
- Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France
- Department of Immunology, Assistance Publique - Hôpitaux de Paris (AP-HP), Georges Pompidou European Hospital, Paris, France
| | - Mathilde Cailliez
- Department of Pediatric Nephrology, Marseille University Hospital, Marseille, France
| | - Aude Servais
- Department of Nephrology, Necker Hospital, Paris, France
| | - Gwenaelle Roussey
- Department of Pediatric Nephrology, Nantes University Hospital, Nantes, France
| | - Véronique Baudouin
- Department of Pediatric Nephrology, Robert Debre Hospital, Paris, France
| | - Stéphane Decramer
- Department of Nephrology, Toulouse University Hospital, Toulouse, France
| | - François Nobili
- Department of Nephrology, Besancon University Hospital, Besancon, France
| | - Alain Wynckel
- Department of Nephrology, Reims University Hospital, Reims, France
| | | | | | - Paula Vieira Martins
- Department of Immunology, Assistance Publique - Hôpitaux de Paris (AP-HP), Georges Pompidou European Hospital, Paris, France
| | - Seppo Meri
- Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
| | - Marie-Agnès Dragon-Durey
- Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France
- Department of Immunology, Assistance Publique - Hôpitaux de Paris (AP-HP), Georges Pompidou European Hospital, Paris, France
| | - Sophie Chauvet
- Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France
- Department of Nephrology, Assistance Publique - Hôpitaux de Paris (AP-HP), Georges Pompidou European Hospital, Paris, France
| | - Véronique Frémeaux-Bacchi
- Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France
- Department of Immunology, Assistance Publique - Hôpitaux de Paris (AP-HP), Georges Pompidou European Hospital, Paris, France
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11
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Canetta P. When a NeF Is Not Enough: Improving Assays in C3 Glomerulopathy. J Am Soc Nephrol 2025; 36:174-176. [PMID: 39774057 PMCID: PMC11801742 DOI: 10.1681/asn.0000000604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
Affiliation(s)
- Pietro Canetta
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
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12
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Bomback AS, Charu V, Fakhouri F. Challenges in the Diagnosis and Management of Immune Complex-Mediated Membranoproliferative Glomerulonephritis and Complement 3 Glomerulopathy. Kidney Int Rep 2025; 10:17-28. [PMID: 39810761 PMCID: PMC11725974 DOI: 10.1016/j.ekir.2024.09.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 09/13/2024] [Accepted: 09/17/2024] [Indexed: 01/16/2025] Open
Abstract
Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and complement 3 glomerulopathy (C3G) are rare, complement-mediated kidney diseases, previously classified under the group of kidney disorders termed membranoproliferative glomerulonephritis (MPGN) type 1, type 2, and type 3. Despite new advances in our understanding of IC-MPGN and C3G, several unmet needs persist in the diagnosis and management of patients with these nephropathies, due in part to their rarity and their overlapping clinical presentations, histologic features, and underlying pathophysiologies. This review summarizes our current understanding of the role of complement in IC-MPGN and C3G, and underlines the key histopathologic differences between the diseases. Using seven illustrative patient cases, we discuss consensus guideline treatment recommendations and the uncertainties, challenges, and considerations regarding the diagnosis and management of patients with IC-MPGN and C3G in clinical practice. The presented cases emphasize the need for a multidisciplinary approach encompassing primary care providers (PCPs), nephrologists, nephropathologists, and laboratory scientists. Key knowledge gaps are evaluated, including differential diagnoses, underlying pathologic mechanisms, and the lack of effective treatments targeting drivers of disease. As the therapeutic landscape evolves, an improved understanding of IC-MPGN and C3G is crucial to identifying optimal targeted-treatment strategies and facilitating a personalized approach to the management of these complex glomerular diseases.
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Affiliation(s)
- Andrew S. Bomback
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Vivek Charu
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Fadi Fakhouri
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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13
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Bomback AS, Daina E, Remuzzi G, Kanellis J, Kavanagh D, Pickering MC, Sunder-Plassmann G, Walker PD, Wang Z, Ahmad Z, Fakhouri F. Efficacy and Safety of Pegcetacoplan in Kidney Transplant Recipients With Recurrent Complement 3 Glomerulopathy or Primary Immune Complex Membranoproliferative Glomerulonephritis. Kidney Int Rep 2025; 10:87-98. [PMID: 39810766 PMCID: PMC11725963 DOI: 10.1016/j.ekir.2024.09.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 09/25/2024] [Accepted: 09/30/2024] [Indexed: 01/16/2025] Open
Abstract
Introduction Complement 3 glomerulopathy (C3G) and primary immune complex membranoproliferative glomerulonephritis (IC-MPGN) have high risks for disease recurrence and allograft loss in transplant kidneys. Pegcetacoplan (targeted complement 3 [C3]/C3b inhibitor) may prevent excessive deposition of C3 and complement 5 [C5] breakdown products and associated renal damage. Methods NOBLE (NCT04572854) is a prospective, phase 2, multicenter, open-label, randomized controlled trial evaluating the efficacy and safety of pegcetacoplan in posttransplant patients with recurrent C3G or IC-MPGN. The primary end point was reduction in C3c staining on renal biopsy at week 12 for patients who received either pegcetacoplan 1080 mg twice weekly by subcutaneous infusion plus standard-of-care (SOC) or SOC only. Results Ten patients received pegcetacoplan and 3 received SOC only through week 12. At week 12, 5 of 10 pegcetacoplan-treated patients (50%) achieved ≥2 orders of magnitude (OOM) reduction in C3 staining (4 of these 5 had 0 staining and absent electron microscopy deposits) and 8 of 10 (80%) achieved ≥1 OOM reduction; 1 of 3 (33%) SOC-only patients showed staining reduction. Mean C3G histology activity score decreased by >54% in 8 of 10 pegcetacoplan-treated patients (80.0%). Pegcetacoplan-treated patients with baseline urine protein-to-creatinine ratio (uPCR) ≥1000 mg/g showed a median (interquartile range [IQR]) 54.4% (-56.33 to -53.95) reduction in proteinuria at week 12. In addition, pegcetacoplan-treated patients showed stable estimated glomerular filtration rate (eGFR), reduced plasma sC5b-9, and increased serum C3. Pegcetacoplan was well-tolerated and most adverse events were mild/moderate. No discontinuations, treatment withdrawals, or deaths were reported. Conclusion NOBLE demonstrated efficacy, safety, and tolerability of pegcetacoplan for patients with posttransplant recurrent C3G and primary IC-MPGN.
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Affiliation(s)
- Andrew S. Bomback
- Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA
| | - Erica Daina
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - John Kanellis
- Department of Nephrology, Monash Health and Centre for Inflammatory Diseases, Clayton, Australia
- Department of Medicine, Monash Medical Centre, Clayton, Australia
| | - David Kavanagh
- National Renal Complement Therapeutics Centre, Newcastle University, UK
| | | | - Gere Sunder-Plassmann
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Patrick D. Walker
- Department of Renal Pathology, Arkana Laboratories, Little Rock, Arkansas, USA
| | - Zhongshen Wang
- Apellis Pharmaceuticals, Inc., Waltham, Massachusetts, USA
| | - Zurish Ahmad
- Apellis Pharmaceuticals, Inc., Waltham, Massachusetts, USA
| | - Fadi Fakhouri
- Lausanne University Hospital, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
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14
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Java A, Fuller L. Establishing the Future Direction of Clinical Outcomes in C3 Glomerulopathy: Perspectives From a Patient and a Physician. Kidney Med 2025; 7:100928. [PMID: 39758154 PMCID: PMC11699595 DOI: 10.1016/j.xkme.2024.100928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2025] Open
Abstract
Complement 3 glomerulopathy (C3G) is an ultra-rare glomerulonephritis caused by dysregulation of the alternative complement pathway. C3G has an estimated incidence of 1-3 cases per million people in the United States. Diagnosing C3G based solely on clinical and laboratory features is challenging because it mimics several other glomerular diseases; therefore, diagnosis requires a kidney biopsy. In the absence of disease-modifying therapies and optimal patient management strategies, C3G poses a significant physical and emotional burden on patients and caregivers. Common symptoms of glomerulonephritis include fatigue, edema, anxiety, and/or depression, which have profound effects on patients' daily lives. Approximately half of all patients progress to kidney failure within 10 years of diagnosis. Encouragingly, the treatment landscape in C3G is poised to change, with several targeted complement inhibitors in late-stage development. This perspectives article explores a patient's journey in C3G and discusses the current and future status of clinical outcomes and patient management from the viewpoints of a practicing nephrologist and a patient.
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Affiliation(s)
- Anuja Java
- Department of Nephrology, Washington University School of Medicine in St. Louis, St. Louis, MO
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15
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Patry C, Webb NJA, Feißt M, Krupka K, Becker J, Bald M, Antoniello B, Bilge I, Gulhan B, Hogan J, Kanzelmeyer N, Ozkaya O, Büscher A, Sellier-Leclerc AL, Shenoy M, Weber LT, Fichtner A, Höcker B, Meier M, Tönshoff B. Kidney transplantation in children and adolescents with C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis: a real-world study within the CERTAIN research network. Pediatr Nephrol 2024; 39:3569-3580. [PMID: 39110227 PMCID: PMC11511764 DOI: 10.1007/s00467-024-06476-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/02/2024] [Accepted: 07/18/2024] [Indexed: 10/26/2024]
Abstract
BACKGROUND Complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40-50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the transplanted kidney. However, there is a lack of published data on clinical outcomes in the pediatric population following transplantation. METHODS In this multicenter longitudinal cohort study of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, we compared the post-transplant outcomes of pediatric patients with C3G (n = 17) or IC-MPGN (n = 3) with a matched case-control group (n = 20). RESULTS Eleven of 20 children (55%) with C3G or IC-MPGN experienced a recurrence within 5 years post-transplant. Patients with C3G or IC-MPGN had a 5-year graft survival of 61.4%, which was significantly (P = 0.029) lower than the 5-year graft survival of 90% in controls; five patients with C3G or IC-MPGN lost their graft due to recurrence during this observation period. Both the 1-year (20%) and the 5-year (42%) rates of biopsy-proven acute rejection episodes were comparable between patients and controls. Complement-targeted therapy with eculizumab, either as prophylaxis or treatment, did not appear to be effective. CONCLUSIONS These data in pediatric patients with C3G or IC-MPGN show a high risk of post-transplant disease recurrence (55%) and a significantly lower 5-year graft survival compared to matched controls with other primary kidney diseases. These data underscore the need for post-transplant patients for effective and specific therapies that target the underlying disease mechanism.
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Affiliation(s)
- Christian Patry
- Heidelberg University, Medical Faculty, Department of Pediatrics I, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany.
| | | | - Manuel Feißt
- Institute of Medical Biometry, University of Heidelberg, Heidelberg, Germany
| | - Kai Krupka
- Heidelberg University, Medical Faculty, Department of Pediatrics I, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany
| | - Jan Becker
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Martin Bald
- Klinikum Stuttgart, Olgahospital, Stuttgart, Germany
| | - Benedetta Antoniello
- Laboratory of Immunopathology and Molecular Biology of the Kidney, Pediatric Research Institute, Department of Women's and Children's Health, Padua University Hospital, Padua, Italy
| | - Ilmay Bilge
- Koç University Hospital, Koç University School of Medicine, Istanbul, Turkey
| | - Bora Gulhan
- Department of Pediatric Nephrology, Hacettepe University, Faculty of Medicine, Ankara, Turkey
| | - Julien Hogan
- Robert Debre Hospital, Department of Pediatric Nephrology, Dialysis, Transplantation, Paris, France
| | - Nele Kanzelmeyer
- Medical School of Hannover, Clinic of Pediatric Nephrology, Hepatology and Metabolic Diseases, Hannover, Germany
| | - Ozan Ozkaya
- İstinye University Hospital, İstinye University School of Medicine, Istanbul, Turkey
| | - Anja Büscher
- University Hospital of Essen, Department of Pediatrics II, University of Duisburg-Essen, Essen, Germany
| | - Anne-Laure Sellier-Leclerc
- Service de Néphrologie Rhumatologie Dermatologie Pédiatrique, Centre de Référence Maladies Rénales Rares "Néphrogones", Hospices Civils de Lyon, Lyon, France
| | - Mohan Shenoy
- Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Lutz T Weber
- Children's and Adolescents's Hospital, University Hospital of Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany
| | - Alexander Fichtner
- Heidelberg University, Medical Faculty, Department of Pediatrics I, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany
| | - Britta Höcker
- Heidelberg University, Medical Faculty, Department of Pediatrics I, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany
| | | | - Burkhard Tönshoff
- Heidelberg University, Medical Faculty, Department of Pediatrics I, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, Heidelberg, 69120, Germany
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16
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Ghani M, Alisan B, Barmas-Alamdari D, Attieh RM, Jhaveri KD. The Difficulties of Treating Complement-3-Mediated Glomerulopathy. Am J Ther 2024; 31:e652-e658. [PMID: 39792491 DOI: 10.1097/mjt.0000000000001763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
BACKGROUND C3 glomerulopathy (C3G) is a rare disease affecting the complement alternative pathway, categorized into dense deposit disease and C3 glomerulonephritis. Dense deposit disease predominantly affects younger individuals, while C3 glomerulonephritis tends to manifest in older populations. The diseases are characterized by dysregulation of the complement alternative pathway, leading to the deposition of complement components in the glomeruli and subsequent renal dysfunction. Notably, the incidence of C3G in the United States is low, with 1-3 cases per 1,000,000 and a prevalence of 5 cases per 1,000,000. AREAS OF UNCERTAINTY Numerous uncertainties persist in comprehending the etiology and pathophysiology of C3G. While biomarkers such as C3 nephritic factor, autoantibodies, and relevant genetic mutations have been identified, their pathogenicity and clinical utility remain unclear. Standard workups involve complement assays and autoantibody panels, yet the definitive diagnostic test remains a kidney biopsy. Nuanced challenges lie in deciphering the sensitivity and specificity of these diagnostic tools, especially in the presence of phenotypical variations among individuals. THERAPEUTIC ADVANCEMENT Current therapeutic approaches, albeit lacking robust evidence, encompass a spectrum ranging from supportive care to targeted B-cell therapy and immunosuppression with mycophenolate mofetil and glucocorticoids. For severe and refractory cases, the monoclonal antibody eculizumab, targeting C5 in the complement cascade, is recommended. These treatments, while offering some relief, pose challenges related to their cost and obtaining insurance approval. Exploratory avenues delve into the potential of plasma exchange and innovative treatments such as oral complement inhibitors, reflecting the ongoing quest for effective therapeutic modalities. Trials investigating various complement inhibitors underscore the dynamic landscape of therapeutic advancements in C3G management. CONCLUSION In conclusion, the article highlights the complexities of C3G management. The need for further understanding, large-scale trials, and ongoing investigations into disease etiology and pathophysiology is emphasized.
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Affiliation(s)
- Maham Ghani
- Northwell, New Hyde Park, NY, Department of Medicine, Manhasset, NY
| | - Bedir Alisan
- Penn State, Milton S Hershey Medical Center, Hershey, PA
| | - Daniel Barmas-Alamdari
- Division of Ophthalmology, Northwell Eye Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY; and
| | - Rose Mary Attieh
- Northwell, New Hyde Park, NY, Department of Medicine, Manhasset, NY
- Division of Kidney Diseases and Hypertension, Glomerular Center at Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY
| | - Kenar D Jhaveri
- Northwell, New Hyde Park, NY, Department of Medicine, Manhasset, NY
- Division of Kidney Diseases and Hypertension, Glomerular Center at Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Great Neck, NY
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17
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Heidenreich K, Goel D, Priyamvada PS, Kulkarni S, Chakurkar V, Khullar D, Singh R, Bale C, Zipfel PF. C3 glomerulopathy: a kidney disease mediated by alternative pathway deregulation. FRONTIERS IN NEPHROLOGY 2024; 4:1460146. [PMID: 39534179 PMCID: PMC11554616 DOI: 10.3389/fneph.2024.1460146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 09/17/2024] [Indexed: 11/16/2024]
Abstract
C3 glomerulopathy (C3G) is an ultra-rare complement-mediated kidney disease caused by to the deregulation of the alternative pathway (AP) of proximal complement. Consequently, all effector loops of the complement are active and can lead to pathologies, such as C3a- and C5a-mediated inflammation, C3b opsonization, surface C3b-mediated AP C3 convertase assembly, C3 cleavage product deposition in the glomerulus, and lytic C5b-9/MAC cell damage. The most common pathologic mechanisms are defective chronic alternative pathway deregulation, mostly occurring in the plasma, often causing C3 consumption, and chronic complement-mediated glomerular damage. C3G develops over several years, and loss of renal function occurs in more than 50% of patients. C3G is triggered by both genetic and autoimmune alterations. Genetic causes include mutations in individual complement genes and chromosomal variations in the form of deletions and duplications affecting genes encoding complement modulators. Many genetic aberrations result in increased AP C3 convertase activity, either due to decreased activity of regulators, increased activity of modulators, or gain-of-function mutations in genes encoding components of the convertase. Autoimmune forms of C3G do also exist. Autoantibodies target individual complement components and regulators or bind to neoepitopes exposed in the central alternative pathway C3 convertase, thereby increasing enzyme activity. Overactive AP C3 convertase is common in C3G patients. Given that C3G is a complement disease mediated by defective alternative pathway action, complement blockade is an emerging concept for therapy. Here, we summarize both the causes of C3G and the rationale for complement inhibition and list the inhibitors that are being used in the most advanced clinical trials for C3G. With several inhibitors in phase II and III trials, it is expected that effectice treatment for C3G will become availabe in the near future.
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Affiliation(s)
| | | | - P. S. Priyamvada
- Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Sagar Kulkarni
- Department of Nephrology, King Edward Memorial Hospital, Pune, Maharashtra, India
| | - Vipul Chakurkar
- Department of Nephrology, King Edward Memorial Hospital, Pune, Maharashtra, India
| | - Dinesh Khullar
- Department of Nephrology and Renal Transplantation, Max Super Speciality Hospital Saket, New Delhi, India
| | - Ravi Singh
- Department of Nephrology and Renal Transplant, Jaypee Hospital, Noida, Uttar Pradesh, India
| | - Charan Bale
- Department of Nephrology, Dr. D.Y. Patil Medical College & Research Centre, Pune, Maharashtra, India
| | - Peter F. Zipfel
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany
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18
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Vivarelli M, Barratt J, Beck LH, Fakhouri F, Gale DP, Goicoechea de Jorge E, Mosca M, Noris M, Pickering MC, Susztak K, Thurman JM, Cheung M, King JM, Jadoul M, Winkelmayer WC, Smith RJH. The role of complement in kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2024; 106:369-391. [PMID: 38844295 DOI: 10.1016/j.kint.2024.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 04/25/2024] [Accepted: 05/22/2024] [Indexed: 06/22/2024]
Abstract
Uncontrolled complement activation can cause or contribute to glomerular injury in multiple kidney diseases. Although complement activation plays a causal role in atypical hemolytic uremic syndrome and C3 glomerulopathy, over the past decade, a rapidly accumulating body of evidence has shown a role for complement activation in multiple other kidney diseases, including diabetic nephropathy and several glomerulonephritides. The number of available complement inhibitor therapies has also increased during the same period. In 2022, Kidney Diseases: Improving Global Outcomes (KDIGO) convened a Controversies Conference, "The Role of Complement in Kidney Disease," to address the expanding role of complement dysregulation in the pathophysiology, diagnosis, and management of various glomerular diseases, diabetic nephropathy, and other forms of hemolytic uremic syndrome. Conference participants reviewed the evidence for complement playing a primary causal or secondary role in progression for several disease states and considered how evidence of complement involvement might inform management. Participating patients with various complement-mediated diseases and caregivers described concerns related to life planning, implications surrounding genetic testing, and the need for inclusive implementation of effective novel therapies into clinical practice. The value of biomarkers in monitoring disease course and the role of the glomerular microenvironment in complement response were examined, and key gaps in knowledge and research priorities were identified.
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Affiliation(s)
- Marina Vivarelli
- Laboratory of Nephrology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
| | - Jonathan Barratt
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Laurence H Beck
- Section of Nephrology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Fadi Fakhouri
- Department of Nephrology, Centre Hospitalier Universitaire, Nantes, France; INSERM UMR S1064, Nantes, France
| | - Daniel P Gale
- Centre for Kidney and Bladder Health, University College London, UK
| | - Elena Goicoechea de Jorge
- Department of Immunology, Ophthalmology and ORL, Complutense University, Madrid, Spain; Area of Chronic Diseases and Transplantation, Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Marta Mosca
- Department of Clinical and Experimental Medicine-Rheumatology Unit, University of Pisa, Pisa, Italy
| | - Marina Noris
- Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica, Italy
| | - Matthew C Pickering
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College, Hammersmith Campus, London, UK
| | - Katalin Susztak
- Division of Nephrology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Joshua M Thurman
- Division of Nephrology and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | | | | | - Michel Jadoul
- Cliniques Universitaires Saint Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Wolfgang C Winkelmayer
- Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Richard J H Smith
- Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; Department of Internal Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; Department of Pediatrics, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
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19
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Andeen NK, Hou J. Diagnostic Challenges and Emerging Pathogeneses of Selected Glomerulopathies. Pediatr Dev Pathol 2024; 27:387-410. [PMID: 38576387 DOI: 10.1177/10935266241237656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/06/2024]
Abstract
Recent progress in glomerular immune complex and complement-mediated diseases have refined diagnostic categories and informed mechanistic understanding of disease development in pediatric patients. Herein, we discuss selected advances in 3 categories. First, membranous nephropathy antigens are increasingly utilized to characterize disease in pediatric patients and include phospholipase A2 receptor (PLA2R), Semaphorin 3B (Sema3B), neural epidermal growth factor-like 1 (NELL1), and protocadherin FAT1, as well as the lupus membranous-associated antigens exostosin 1/2 (EXT1/2), neural cell adhesion molecule 1 (NCAM1), and transforming growth factor beta receptor 3 (TGFBR3). Second, we examine advances in techniques for paraffin and light chain immunofluorescence (IF), including the former's function as a salvage technique and their necessity for diagnosis in adolescent cases of membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) and proliferative glomerulonephritis with monotypic Ig deposits (PGNMID), respectively. Finally, progress in understanding the roles of complement in pediatric glomerular disease is reviewed, with specific attention to overlapping clinical, histologic, and genetic or functional alternative complement pathway (AP) abnormalities among C3 glomerulopathy (C3G), infection-related and post-infectious GN, "atypical" post-infectious GN, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS).
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Affiliation(s)
- Nicole K Andeen
- Oregon Health & Science University, Department of Pathology and Laboratory Medicine, Portland, OR, USA
| | - Jean Hou
- Cedars-Sinai Medical Center, Department of Pathology, Los Angeles, CA, USA
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20
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Ueda C, Horinouchi T, Inoki Y, Ichikawa Y, Tanaka Y, Kitakado H, Kondo A, Sakakibara N, Nagano C, Yamamura T, Fujimura J, Kamiyoshi N, Ishimori S, Ninchoji T, Kaito H, Shima Y, Iijima K, Nozu K, Yoshikawa N. Clinical characteristics and outcomes of immune-complex membranoproliferative glomerulonephritis and C3 glomerulopathy in Japanese children. Pediatr Nephrol 2024; 39:2679-2689. [PMID: 38662234 PMCID: PMC11272671 DOI: 10.1007/s00467-024-06377-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 03/29/2024] [Accepted: 04/01/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND Membranoproliferative glomerulonephritis (MPGN) can be divided into immune-complex MPGN (IC-MPGN) and C3 glomerulopathy (C3G), which includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These conditions result from abnormalities in different complement pathways and may lead to different prognoses. However, there are limited studies describing the respective clinical courses. METHODS In this study, Japanese pediatric patients diagnosed with MPGN based on kidney biopsies conducted between February 2002 and December 2022 were reclassified as having IC-MPGN or C3G (DDD or C3GN). We retrospectively analyzed the clinical characteristics and outcomes of these patients. RESULTS Out of 25 patients with MPGN, three (12.0%) were diagnosed with DDD, 20 (80.0%) with C3GN, and two (8.0%) with IC-MPGN. There were 13 (65.0%) patients and one (33.3%) patient in remission after treatment for C3GN and DDD, respectively, and no patients with IC-MPGN achieved remission. The median follow-up period was 5.3 (2.5-8.9) years, and none of the patients in either group progressed to an estimated glomerular filtration rate < 15 ml/min/1.73 m2. Patients with C3GN presenting mild to moderate proteinuria (n = 8) received a renin-angiotensin system inhibitor (RAS-I) alone, and these patients exhibited a significant decrease in the urinary protein creatinine ratio and a notable increase in serum C3 levels at the last follow-up. CONCLUSIONS Most patients with MPGN were diagnosed with C3GN. The remission rate for C3GN was high, and no patients developed kidney failure during the approximately 5-year follow-up. Additionally, patients with C3GN with mild to moderate proteinuria had good outcomes with RAS-I alone, but continued vigilance is necessary to determine long-term prognosis.
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Affiliation(s)
- Chika Ueda
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Tomoko Horinouchi
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan.
| | - Yuta Inoki
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Yuta Ichikawa
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Yu Tanaka
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Hideaki Kitakado
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Atsushi Kondo
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Nana Sakakibara
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - China Nagano
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Tomohiko Yamamura
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Junya Fujimura
- Department of Pediatrics, Kakogawa Central City Hospital, 439 Honmachi, Kakogawa-Cho, Kakogawa, 675-8611, Japan
| | - Naohiro Kamiyoshi
- Department of Pediatrics, Japanese Red Cross Society Himeji Hospital, 1-12-1 Shimoteno, Himeji, 670-8540, Japan
| | - Shingo Ishimori
- Department of Pediatrics, Takatsuki General Hospital, 1-3-13 Kosobe‑cho, Takatsuki, 569-1192, Japan
| | - Takeshi Ninchoji
- Department of Pediatrics, Harima-Himeji General Medical Center, 3-264 Kamiyacho, Himeji, 670-8560, Japan
| | - Hiroshi Kaito
- Department of Nephrology, Hyogo Prefectural Kobe Children's Hospital, 1-6-7, Minatojima-Minamimachi, Chuo-Ku, Kobe, 650-0047, Japan
| | - Yuko Shima
- Department of Pediatrics, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan
| | - Kazumoto Iijima
- Hyogo Prefectural Kobe Children's Hospital, 1-6-7, Minatojima-Minamimachi, Chuo-Ku, Kobe, 650-0047, Japan
- Department of Advanced Pediatric Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Norishige Yoshikawa
- Clinical Research Center, Takatsuki General Hospital, 1-3-13 Kosobe-Cho, Takatsuki, 569-1192, Japan
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21
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Mirioglu S, Cebeci E, Yazici H, Derici U, Sahin G, Coban G, Eren N, Gungor O, Dede F, Dincer T, Turkmen K, Basturk T, Duranay M, Arikan H, Tunca O, Elcioglu OC, Tatar E, Aydin Z, Oygar D, Demir S, Tanrisev M, Kurultak I, Oruc A, Turkmen A, Akcay OF, Cetinkaya H, Ozturk S. Prognostic factors and validation of the histologic chronicity score for C3 glomerulopathy: a registry analysis. Clin Kidney J 2024; 17:sfae077. [PMID: 39421234 PMCID: PMC11483614 DOI: 10.1093/ckj/sfae077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Indexed: 10/19/2024] Open
Abstract
Background Data on the prognostic factors for C3 glomerulopathy (C3G) are limited, and validation of the new C3G histologic index (C3G-HI) in different settings is still needed. We aimed to evaluate the chronicity score of C3G-HI and probable prognostic factors in our population. Methods In this registry study, 74 patients from 20 centers with adequate follow-up data were included. Total chronicity score (TCS) was calculated according to percentages of glomerulosclerosis, interstitial fibrosis, tubular atrophy, and presence of arterio- and arteriolosclerosis. Primary composite outcome was defined as doubling of serum creatinine from baseline, undergoing dialysis or transplantation, development of stage 5 chronic kidney disease, or death. Results Median age was 34 [interquartile range (IQR) 24-46] years, and 39 patients (52.7%) were male. Median follow-up duration was 36 (IQR 12-60) months, and median TCS was 3 (IQR 1-5). Overall, 19 patients (25.7%) experienced primary composite outcome. Multivariate Cox regression model showed that only hemoglobin [adjusted HR (aHR) 0.67, 95% confidence interval 0.46-0.97, P = .035] predicted primary composite outcome, and TCS fell short of the statistical significance (aHR 1.26, 0.97-1.64, P = .08). Receiver operating characteristic analysis demonstrated that TCS showed an area under the curve value of 0.68 (0.56-0.78, P = .028) in discriminating primary composite outcome at 3 years, and 3-year kidney survival was lower in patients with TCS ≥4 (72.4%) compared with TCS <4 (91.1%) in Kaplan-Meier analysis (P = .036). Conclusions Low hemoglobin levels predicted dismal outcomes in patients with C3G. TCS ≥4 was associated with a worse 3-year kidney survival, which validated the 3-year prognostic value of the TCS of C3G-HI in our population.
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Affiliation(s)
- Safak Mirioglu
- Division of Nephrology, Bezmialem Vakif University Faculty of Medicine, Istanbul, Turkey
| | - Egemen Cebeci
- Division of Nephrology, Istanbul Haseki Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Halil Yazici
- Division of Nephrology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Ulver Derici
- Division of Nephrology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Gulizar Sahin
- Division of Nephrology, Sultan 2. Abdulhamid Han Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Ganime Coban
- Department of Pathology, Bezmialem Vakif University Faculty of Medicine, Istanbul, Turkey
| | - Necmi Eren
- Division of Nephrology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Ozkan Gungor
- Division of Nephrology, Kahramanmaras Sutcu Imam University Faculty of Medicine, Kahramanmaras, Turkey
| | - Fatih Dede
- Division of Nephology, Ankara Bilkent City Hospital, University of Health Sciences, Ankara, Turkey
| | - Tamer Dincer
- Division of Nephrology, Istanbul University-Cerrahpasa Cerrahpasa Faculty of Medicine, Istanbul, Turkey
| | - Kultigin Turkmen
- Division of Nephrology, Necmettin Erbakan University Faculty of Medicine, Konya, Turkey
| | - Taner Basturk
- Division of Nephrology, Hamidiye Etfal Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Murat Duranay
- Division of Nephrology, Ankara Training and Research Hospital, University of Health Sciences, Ankara, Turkey
| | - Hakki Arikan
- Division of Nephrology, Marmara University Faculty of Medicine, Istanbul, Turkey
| | - Onur Tunca
- Division of Nephrology, Afyonkarahisar Health Sciences University Faculty of Medicine, Afyonkarahisar, Turkey
| | - Omer Celal Elcioglu
- Division of Nephrology, Bezmialem Vakif University Faculty of Medicine, Istanbul, Turkey
| | - Erhan Tatar
- Division of Nephrology, Bozyaka Training and Research Hospital, University of Health Sciences, Izmir, Turkey
| | - Zeki Aydin
- Division of Nephrology, Darica Farabi Training and Research Hospital, University of Health Sciences, Kocaeli, Turkey
| | - Deren Oygar
- Division of Nephrology, Dr Burhan Nalbantoglu State Hospital, Lefkosa, Cyprus
| | - Serap Demir
- Division of Nephrology, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Mehmet Tanrisev
- Division of Nephrology, Tepecik Training and Research Hospital, University of Health Sciences, Izmir, Turkey
| | - Ilhan Kurultak
- Division of Nephrology, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Aysegul Oruc
- Division of Nephrology, Bursa Uludag University Faculty of Medicine, Bursa, Turkey
| | - Aydin Turkmen
- Division of Nephrology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Omer Faruk Akcay
- Division of Nephrology, Gazi University Faculty of Medicine, Ankara, Turkey
| | - Hakki Cetinkaya
- Division of Nephrology, Sultan 2. Abdulhamid Han Training and Research Hospital, University of Health Sciences, Istanbul, Turkey
| | - Savas Ozturk
- Division of Nephrology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
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22
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Tarragón B, Peleg Y, Jagannathan G, Sekulic M, Chang JH, Cohen DJ, Crew RJ, Dube GK, Fernandez HE, Husain SA, Mohan S, Morris HK, Appel GB, Jadav P, Santoriello D, Kudose S, Stokes MB, Batal I, Bomback AS. C3 Glomerulopathy Recurs Early after Kidney Transplantation in Serial Biopsies Performed within the First 2 Years after Transplantation. Clin J Am Soc Nephrol 2024; 19:1005-1015. [PMID: 39116277 PMCID: PMC11321730 DOI: 10.2215/cjn.0000000000000474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 06/03/2024] [Indexed: 06/09/2024]
Abstract
Background C3 glomerulopathy (C3G), which encompasses C3GN and dense deposit disease (DDD), results from dysregulation of the alternative complement pathway. Data on disease recurrence after kidney transplantation are limited, and details on histologic features of recurrent C3G are scarce. We aimed to evaluate C3G recurrence in the allograft, with a focus on histologic presentation and progression. Methods We retrospectively analyzed 18 patients with native kidney failure attributed to C3G (12 C3GN and six DDD), who received a kidney transplant from January 2016 to January 2023. Demographic, genetic, clinical, and histologic data were studied. The NanoString 770 genes PanCancer Immune Profiling Panel was used for transcriptomic analysis. Disease recurrence was the primary outcome. Results During a median (interquartile range) follow-up period of 37 (18–56) months, C3G recurrence occurred in 16 (89%) patients (11 with C3GN and five with DDD) at a median (interquartile range) of 33 (13–141) days after transplantation. Over a third (38%) of recurrent cases were detected in protocol biopsies, and only 31% of patients presented with >300 mg/g of proteinuria. Recurrence in index biopsies was mainly established through a combination of immunofluorescence and electron microscopy findings, while it showed only subtle histologic alterations and no characteristic transcriptomic signals. Over time, histologic chronicity indices increased, but all the allografts were functioning at the end of follow-up. Patients with recurrence of C3GN and DDD showed overlapping immunofluorescence and electron microscopy findings and had similar recurrence rate and time to recurrence. Conclusions Most of the patients with native kidney failure attributed to C3G developed disease recurrence very early after kidney transplantation, usually with minimal proteinuria, mild histologic alterations, and favorable short-term allograft survival. Immunofluorescence and electron microscopy played a crucial role in detecting early, subclinical recurrence of C3GN and DDD, which showed significant overlapping features.
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Affiliation(s)
- Blanca Tarragón
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Yonatan Peleg
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Geetha Jagannathan
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Miroslav Sekulic
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Jae-Hyung Chang
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - David J. Cohen
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Russell J. Crew
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Geoffrey K. Dube
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Hilda E. Fernandez
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Syed Ali Husain
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Sumit Mohan
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Heather K. Morris
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Gerald B. Appel
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Paresh Jadav
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
| | - Dominick Santoriello
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Satoru Kudose
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - M. Barry Stokes
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Ibrahim Batal
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Andrew S. Bomback
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
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23
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Kovala M, Seppälä M, Wojnicki M, Honkanen E, Meri S, Kaartinen K, Räisänen-Sokolowski A. Unsupervised Clustering of Membranoproliferative Glomerulonephritis and C3 Glomerulopathy Patients Discovers Distinct Patient Groups unlike the Current Classification. Nephron Clin Pract 2024; 148:734-743. [PMID: 38964287 DOI: 10.1159/000539893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 06/12/2024] [Indexed: 07/06/2024] Open
Abstract
INTRODUCTION Membranoproliferative glomerulonephritis is currently divided into immunoglobulin-mediated glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G); however, the patients often overlap with histology, complement, clinical and prognostic factors. Our aim was to investigate if an unsupervised clustering method finds different patient groups in 44 IC-MPGN/C3G patients using only histological and clinical data available in everyday clinical work. METHODS Primary IC-MPGN/C3G adult patients were included whose diagnostic (baseline) native biopsy was obtained in 2006-2017. The biopsies were reassessed and the clinical data at baseline and during follow-up were obtained from the medical records. There were 39 baseline histological and clinical variables included in the unsupervised clustering. Follow-up information was combined with the clustering results. RESULTS The clustering resulted in two clusters (n = 24 and n = 20 patients for clusters 1-2, respectively), where cluster 1 had a significantly higher baseline plasma creatinine (mean 213 vs. 104, respectively, p value <0.001) and a lower baseline eGFR than cluster 2 (mean 37 vs. 70, respectively, p value <0.001). Regarding histology, chronic changes such as lobulated glomeruli, mesangial matrix expansion, and glomeruli double contours were more prevalent in cluster 1 (p value <0.001). Biopsy morphology was more often crescentic and membranoproliferative in cluster 1 (p value <0.001). Although the differences were insignificant, cluster 1 patients were in dialysis in the last follow-up or had a progressive disease more often than cluster 2 patients (21% vs. 5%, 38% vs. 10%). CONCLUSIONS Our results indicate that these patients share greater similarity than the current classification IC-MPGN versus C3G indicates.
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Affiliation(s)
- Marja Kovala
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Minna Seppälä
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Mikolaj Wojnicki
- Department of Computer Science, Aalto University, Espoo, Finland
| | - Eero Honkanen
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Seppo Meri
- Department of Bacteriology and Immunology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Kati Kaartinen
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Anne Räisänen-Sokolowski
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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24
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Anderson H, Van Voorthuizen M, O'Donnell J, Beck S. C3 concentrations can be normal in patients with C3 glomerulopathy secondary to C3 nephritic factor. J Clin Pathol 2024; 77:503-506. [PMID: 38538072 DOI: 10.1136/jcp-2023-209319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 03/07/2024] [Indexed: 06/21/2024]
Abstract
C3 glomerulopathy (C3G) is a rare kidney disease caused by the glomerular deposition of C3 fragments secondary to alternative pathway complement dysregulation. C3 nephritic factors (C3Nef) are the most common acquired cause, and their detection has treatment and prognostic implications. Although C3 concentration can be normal in the presence of C3Nef, many laboratories will only perform C3Nef testing when C3 is low. We performed a retrospective study of all positive C3Nef results from the authors' laboratory since 2015 and found that two of the four patients with positive C3Nef and biopsy-confirmed C3G had normal C3 concentrations. This may be in part due to limitations in commercial C3 testing methods which use anti-C3c antisera directed against both C3 breakdown products and native C3. A normal C3 concentration should not preclude C3Nef testing in the appropriate clinical context.
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Affiliation(s)
- Hamish Anderson
- Immunology, Te Whatu Ora-Health New Zealand Canterbury Health Laboratories, Christchurch, New Zealand
| | - Mark Van Voorthuizen
- Immunology, Te Whatu Ora-Health New Zealand Canterbury Health Laboratories, Christchurch, New Zealand
| | - John O'Donnell
- Immunology, Te Whatu Ora-Health New Zealand Canterbury Health Laboratories, Christchurch, New Zealand
| | - Sarah Beck
- Immunology, Te Whatu Ora-Health New Zealand Canterbury Health Laboratories, Christchurch, New Zealand
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25
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van Schaik M, de Vries AP, Bemelman FJ, Rabelink TJ, Trouw LA, van Kooten C, Teng YKO. Clinical Remission and Reduction of Circulating Nephritic Factors by Combining Rituximab With Belimumab in a Case of Complement Factor 3 Glomerulopathy. Kidney Int Rep 2024; 9:1919-1922. [PMID: 38899188 PMCID: PMC11184254 DOI: 10.1016/j.ekir.2024.02.1402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 02/16/2024] [Accepted: 02/19/2024] [Indexed: 06/21/2024] Open
Affiliation(s)
- Mieke van Schaik
- Center of Expertise for Lupus, Vasculitis and Complement-mediated Systemic disease (LuVaCs), Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Aiko P.J. de Vries
- Department of Nephrology and Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Frederike J. Bemelman
- Department of Nephrology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Ton J. Rabelink
- Center of Expertise for Lupus, Vasculitis and Complement-mediated Systemic disease (LuVaCs), Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Leendert A. Trouw
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Cees van Kooten
- Center of Expertise for Lupus, Vasculitis and Complement-mediated Systemic disease (LuVaCs), Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Yoe Kie Onno Teng
- Center of Expertise for Lupus, Vasculitis and Complement-mediated Systemic disease (LuVaCs), Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
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26
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Günay N, Dursun İ, Gökçe İ, Akbalık Kara M, Tekcan D, Çiçek N, Torun Bayram M, Koyun M, Dinçel N, Dursun H, Saygılı S, Yürük Yıldırım ZN, Yüksel S, Dönmez O, Yel S, Demircioğlu Kılıç B, Aydoğ Ö, Atmış B, Çaltık Yılmaz A, Bakkaloğlu SA, Aytaç MB, Taşdemir M, Kasap Demir B, Soylu A, Çomak E, Kantar Özşahin A, Kaçar A, Canpolat N, Yılmaz A, Girişgen İ, Akkoyunlu KB, Alpay H, Poyrazoğlu HM. Complement gene mutations in children with C3 glomerulopathy: do they affect the response to mycophenolate mofetil? Pediatr Nephrol 2024; 39:1435-1446. [PMID: 38041748 DOI: 10.1007/s00467-023-06231-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 11/07/2023] [Accepted: 11/07/2023] [Indexed: 12/03/2023]
Abstract
BACKGROUND C3 glomerulopathy (C3G) is a complement-mediated disease. Although genetic studies are not required for diagnosis, they are valuable for treatment planning and prognosis prediction. The aim of this study is to investigate the clinical phenotypes, kidney survival, and response to mycophenolate mofetil (MMF) treatment in pediatric C3G patients with and without mutations in complement-related genes. METHODS Sixty pediatric C3G patients were included, divided into two groups based on complement-related gene mutations. Demographic and clinical-pathological findings, treatment modalities, and outcome data were compared, and Kaplan-Meier analysis was performed for kidney survival. RESULTS Out of the 60 patients, 17 had mutations. The most common mutation was in the CFH gene (47%). The mean age at diagnosis was higher in the group with mutation (12.9 ± 3.6 vs. 11.2 ± 4.1 years, p = 0.039). While the patients without mutation most frequently presented with nephritic syndrome (44.2%), the mutation group was most likely to have asymptomatic urinary abnormalities (47.1%, p = 0.043). Serum parameters and histopathological characteristics were similar, but hypoalbuminemia was more common in patients without mutation. During 45-month follow-up,10 patients progressed to chronic kidney disease stage 5 (CKD5), with 4 having genetic mutation. The time to develop CKD5 was longer in the mutation group but not significant. MMF treatment had no effect on progression in either group. CONCLUSIONS This study is the largest pediatric C3G study examining the relationship between genotype and phenotype. We showed that the mutation group often presented with asymptomatic urinary abnormalities, was diagnosed relatively late but was not different from the without mutation group in terms of MMF treatment response and kidney survival.
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Affiliation(s)
- Neslihan Günay
- Department of Pediatric Nephrology, Kayseri City Training and Research Hospital, Kayseri, Turkey
| | - İsmail Dursun
- Department of Pediatric Nephrology, Erciyes University Medical Faculty, Kayseri, Turkey.
| | - İbrahim Gökçe
- Department of Pediatric Nephrology, Marmara University Medical Faculty, Istanbul, Turkey
| | - Mehtap Akbalık Kara
- Department of Pediatric Nephrology, Gaziantep University Medical Faculty, Gaziantep, Turkey
| | - Demet Tekcan
- Department of Pediatric Nephrology, Ondokuz Mayıs University Medical Faculty, Samsun, Turkey
| | - Neslihan Çiçek
- Department of Pediatric Nephrology, Marmara University Medical Faculty, Istanbul, Turkey
| | - Meral Torun Bayram
- Dokuz Eylül University Medical Faculty, Department of Pediatric Nephrology, İzmir, Turkey
| | - Mustafa Koyun
- Department of Pediatric Nephrology, Akdeniz University Medical Faculty, Antalya, Turkey
| | - Nida Dinçel
- Behçet Uz Pediatric Diseases Training and Research Hospital, Pediatric Nephrology Clinic, İzmir, Turkey
| | - Hasan Dursun
- Prof. Dr. Cemil, Taşcıoğlu City Hospital Pediatric Nephrology Clinic, Istanbul, Turkey
| | - Seha Saygılı
- Department of Pediatric Nephrology, İstanbul University Cerrahpaşa Medical Faculty, Istanbul, Turkey
| | | | - Selçuk Yüksel
- Department of Pediatric Nephrology, Pamukkale University Medical Faculty, Denizli, Turkey
| | - Osman Dönmez
- Department of Pediatric Nephrology, Uludağ University Medical Faculty, Bursa, Turkey
| | - Sibel Yel
- Department of Pediatric Nephrology, Erciyes University Medical Faculty, Kayseri, Turkey
| | | | - Özlem Aydoğ
- Department of Pediatric Nephrology, Ondokuz Mayıs University Medical Faculty, Samsun, Turkey
| | - Bahriye Atmış
- Department of Pediatric Nephrology, Çukurova University Medical Faculty, Adana, Turkey
| | - Aysun Çaltık Yılmaz
- Department of Pediatric Nephrology, Ankara Baskent University, Ankara, Turkey
| | - Sevcan A Bakkaloğlu
- Department of Pediatric Nephrology, Gazi University Medical Faculty, Ankara, Turkey
| | - Mehmet Baha Aytaç
- Department of Pediatric Nephrology, Kocaeli University Medical Faculty, Kocaeli, Turkey
| | - Mehmet Taşdemir
- Department of Pediatric Nephrology, İstinye University Medical Faculty, Istanbul, Turkey
| | - Belde Kasap Demir
- Medical Faculty Division of Pediatric Nephrology, İzmir Katip Çelebi University, İzmir, Turkey
| | - Alper Soylu
- Dokuz Eylül University Medical Faculty, Department of Pediatric Nephrology, İzmir, Turkey
| | - Elif Çomak
- Department of Pediatric Nephrology, Akdeniz University Medical Faculty, Antalya, Turkey
| | - Aslı Kantar Özşahin
- Behçet Uz Pediatric Diseases Training and Research Hospital, Pediatric Nephrology Clinic, İzmir, Turkey
| | - Alper Kaçar
- Prof. Dr. Cemil, Taşcıoğlu City Hospital Pediatric Nephrology Clinic, Istanbul, Turkey
| | - Nur Canpolat
- Department of Pediatric Nephrology, İstanbul University Cerrahpaşa Medical Faculty, Istanbul, Turkey
| | - Alev Yılmaz
- İstanbul Faculty of Medicine, Department of Pediatric Nephrology, İstanbul University, Istanbul, Turkey
| | - İlknur Girişgen
- Department of Pediatric Nephrology, Pamukkale University Medical Faculty, Denizli, Turkey
| | | | - Harika Alpay
- Department of Pediatric Nephrology, Marmara University Medical Faculty, Istanbul, Turkey
| | - Hakan M Poyrazoğlu
- Department of Pediatric Nephrology, Erciyes University Medical Faculty, Kayseri, Turkey
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Wooden B, Nester CM, Bomback AS. Update on C3 Glomerulopathy. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:223-233. [PMID: 39004462 DOI: 10.1053/j.akdh.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 05/13/2024] [Accepted: 05/20/2024] [Indexed: 07/16/2024]
Abstract
C3 glomerulopathy (C3G) is a rare disorder marked by deposition of C3 in the glomerulus, resulting in damage to the glomerular filtration unit and presenting with features of the nephritic and nephrotic syndromes. Fundamentally, C3G is caused by dysregulation of the alternative pathway of the complement cascade, either due to genetic variants or acquired humoral factors. Despite significant advances in recent years in the understanding of the underlying mechanisms and culprit lesions that result in the development of C3G, treatment options remain severely limited, and the prognosis is often poor. Fortunately, a number of anticomplement therapies are emerging from the drug development pipeline, with several in late-stage testing in patients with C3G, and there is hope that we will soon have more targeted options for managing patients with this devastating disease. In this review, we provide an overview of C3G, as well as summarizing the evidence for current treatments and detailing the clinical trials that are currently underway.
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Affiliation(s)
- Benjamin Wooden
- Division of Nephrology, Department of Medicine, Columbia University, New York, NY.
| | - Carla M Nester
- Division of Nephrology, Department of Medicine, University of Iowa, Iowa City, IA
| | - Andrew S Bomback
- Division of Nephrology, Department of Medicine, Columbia University, New York, NY
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28
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Watanabe-Kusunoki K, Anders HJ. Balancing efficacy and safety of complement inhibitors. J Autoimmun 2024; 145:103216. [PMID: 38552408 DOI: 10.1016/j.jaut.2024.103216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/17/2024] [Accepted: 03/26/2024] [Indexed: 05/15/2024]
Abstract
Complement inhibitors have been approved for several immune-mediated diseases and they are considered the next paradigm-shifting approach in the treatment of glomerulonephritis. The hierarchical organization of the complement system offers numerous molecular targets for therapeutic intervention. However, complement is an integral element of host defense and therefore complement inhibition can be associated with serious infectious complications. Here we give a closer look to the hierarchical complement system and how interfering with proximal versus distal or selective versus unselective molecular targets could determine efficacy and safety. Furthermore, we propose to consider the type of disease, immunological activity, and patient immunocompetence when stratifying patients, e.g., proximal/unselective targets for highly active and potentially fatal diseases while distal and selective targets may suit more chronic disease conditions with low or moderate disease activity requiring persistent complement blockade in patients with concomitant immunodeficiency. Certainly, there exists substantial promise for anti-complement therapeutics. However, balancing efficacy and safety will be key to establish powerful treatment effects with minimal adverse events, especially when complement blockade is continued over longer periods of time in chronic disorders.
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Affiliation(s)
- Kanako Watanabe-Kusunoki
- Renal Division, Department of Medicine IV, Ludwig-Maximilians (LMU) University Hospital, LMU Munich, Germany; Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hans-Joachim Anders
- Renal Division, Department of Medicine IV, Ludwig-Maximilians (LMU) University Hospital, LMU Munich, Germany.
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29
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Zanchi C, Locatelli M, Cerullo D, Aumiller V, Corna D, Rottoli D, Schubert S, Noris M, Tomasoni S, Remuzzi G, Zoja C, Benigni A. Efficacy of GalNAc C3 siRNAs in factor H-deficient mice with C3 glomerulopathy. Mol Immunol 2024; 168:10-16. [PMID: 38368725 DOI: 10.1016/j.molimm.2024.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 01/17/2024] [Accepted: 02/12/2024] [Indexed: 02/20/2024]
Abstract
Complement alternative pathway (AP) dysregulation drives C3 glomerulopathy (C3G), a rare renal disorder characterized by glomerular C3 deposition and glomerular damage, for which no effective treatments are available. Blockade of complement C3 is emerging as a viable therapeutic option. In an earlier study we showed that SLN500, a small interfering RNA targeting liver C3 synthesis, was able to limit AP dysregulation and glomerular C3d deposits in mice with partial factor H (FH) deficiency (Cfh+/- mice). Here, we assessed the pharmacological effects of SLN501 - an optimized SLN500 version - in mice with complete FH deficiency (Cfh-/- mice) that exhibit a more severe C3G phenotype. SLN501 effectively prevented liver C3 synthesis, thus limiting AP dysregulation, glomerular C3d deposits and the development of ultrastructural alterations. These data provide firm evidence of the use of siRNA-mediated liver C3 gene silencing as a potential therapy for treating C3G patients with either partial or complete FH loss of function.
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Affiliation(s)
- Cristina Zanchi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Monica Locatelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Domenico Cerullo
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | | | - Daniela Corna
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Daniela Rottoli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | | | - Marina Noris
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Susanna Tomasoni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Carlamaria Zoja
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
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Obata S, Vaz de Castro PAS, Riella LV, Cravedi P. Recurrent C3 glomerulopathy after kidney transplantation. Transplant Rev (Orlando) 2024; 38:100839. [PMID: 38412598 DOI: 10.1016/j.trre.2024.100839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/17/2024] [Accepted: 02/19/2024] [Indexed: 02/29/2024]
Abstract
The complement system is part of innate immunity and is pivotal in protecting the body against pathogens and maintaining host homeostasis. Activation of the complement system is triggered through multiple pathways, including antibody deposition, a mannan-binding lectin, or activated complement deposition. C3 glomerulopathy (C3G) is a rare glomerular disease driven by complement dysregulation with high post-transplantation recurrence rates. Its treatment is mainly based on immunosuppressive therapies, specifically mycophenolate mofetil and glucocorticoids. Recent years have seen significant progress in understanding complement biology and its role in C3G pathophysiology. New complement-tergeting treatments have been developed and initial trials have shown promising results. However, challenges persist in C3G, with recurrent post-transplantation cases leading to suboptimal outcomes. This review discusses the pathophysiology and management of C3G, with a focus on its recurrence after kidney transplantation.
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Affiliation(s)
- Shota Obata
- Precision Immunology Institute, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Pedro A S Vaz de Castro
- Interdisciplinary Laboratory of Medical Investigation, Unit of Pediatric Nephrology, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Brazil
| | - Leonardo V Riella
- Division of Nephrology and Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States of America
| | - Paolo Cravedi
- Precision Immunology Institute, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
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31
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Catanese L, Rupprecht H, Huber TB, Lindenmeyer MT, Hengel FE, Amann K, Wendt R, Siwy J, Mischak H, Beige J. Non-Invasive Biomarkers for Diagnosis, Risk Prediction, and Therapy Guidance of Glomerular Kidney Diseases: A Comprehensive Review. Int J Mol Sci 2024; 25:3519. [PMID: 38542491 PMCID: PMC10970781 DOI: 10.3390/ijms25063519] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/13/2024] [Accepted: 03/18/2024] [Indexed: 04/09/2025] Open
Abstract
Effective management of glomerular kidney disease, one of the main categories of chronic kidney disease (CKD), requires accurate diagnosis, prognosis of progression, assessment of therapeutic efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for the assessment of specific aspects of glomerular diseases have been reported in the literature. Though, the vast majority of these have not been implemented in clinical practice or are not available on a global scale due to limited access, missing medical infrastructure, or economical as well as political reasons. The aim of this review is to compile all currently available information on the diagnostic, prognostic, and predictive biomarkers currently available for the management of glomerular diseases, and provide guidance on the application of these biomarkers. As a result of the compiled evidence for the different biomarkers available, we present a decision tree for a non-invasive, biomarker-guided diagnostic path. The data currently available demonstrate that for the large majority of patients with glomerular diseases, valid biomarkers are available. However, despite the obvious disadvantages of kidney biopsy, being invasive and not applicable for monitoring, especially in the context of rare CKD etiologies, kidney biopsy still cannot be replaced by non-invasive strategies.
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Affiliation(s)
- Lorenzo Catanese
- Department of Nephrology, Angiology and Rheumatology, Klinikum Bayreuth GmbH, 95445 Bayreuth, Germany; (L.C.); (H.R.)
- Kuratorium for Dialysis and Transplantation (KfH) Bayreuth, 95445 Bayreuth, Germany
- Department of Nephrology, Medizincampus Oberfranken, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Harald Rupprecht
- Department of Nephrology, Angiology and Rheumatology, Klinikum Bayreuth GmbH, 95445 Bayreuth, Germany; (L.C.); (H.R.)
- Kuratorium for Dialysis and Transplantation (KfH) Bayreuth, 95445 Bayreuth, Germany
- Department of Nephrology, Medizincampus Oberfranken, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Tobias B. Huber
- III Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; (T.B.H.); (M.T.L.); (F.E.H.)
| | - Maja T. Lindenmeyer
- III Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; (T.B.H.); (M.T.L.); (F.E.H.)
| | - Felicitas E. Hengel
- III Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; (T.B.H.); (M.T.L.); (F.E.H.)
| | - Kerstin Amann
- Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | - Ralph Wendt
- Division of Nephrology, St. Georg Hospital, 04129 Leipzig, Germany;
| | - Justyna Siwy
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany; (J.S.); (H.M.)
| | - Harald Mischak
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany; (J.S.); (H.M.)
| | - Joachim Beige
- Division of Nephrology, St. Georg Hospital, 04129 Leipzig, Germany;
- Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, 06108 Halle, Germany
- Kuratorium for Dialysis and Transplantation (KfH) Leipzig, 04129 Leipzig, Germany
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Honma S, Sato N, Sakaguchi R, Hashiguchi A, Uesugi N, Nakamura Y, Sasano H, Joh K. Morphological and etiological analyses of C3 and non-C3 glomerulonephritis in primary membranoproliferative glomerulonephritis using periodic acid-methenamine silver stain electron microscopy: a retrospective multicentered study. Med Mol Morphol 2024; 57:23-34. [PMID: 37823929 DOI: 10.1007/s00795-023-00370-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 08/23/2023] [Indexed: 10/13/2023]
Abstract
This study elucidated the etiology of C3 glomerulonephritis (C3GN) and non-C3GN with primary membranoproliferative glomerulonephritis (MPGN) using transmission electron microscopy (TEM) and periodic acid-methenamine silver stain (PAM-EM). Thirty-one primary MPGN cases were analyzed by TEM and PAM-EM to distinguish among MPGN I, MPGN II, MPGN III Burkholder subtype (MPGN IIIB), and Anders and Strife subtype (MPGN IIIA/S). Each case was also classified into C3GN or non-C3GN according to the standard C3GN definition using immunostaining. Four cases of MPGN II met C3 glomerulopathy; whereas, four cases of MPGN IIIB did not meet C3 glomerulopathy. Seven of 11 cases (64%) of MPGN I without GBM disruption and 7 of 12 cases (58%) of MPGN IIIA/S with GBM disruption met the non-C3GN criteria with significant immunoglobulins' deposition. Regardless of the C3GN or non-C3GN diagnosis, the deposits in primary MPGN I and MPGN IIIA/S exhibited ill-defined, amorphous, and foggy characteristics similar to those found in postinfectious GN but were different from immune complex (IC) deposits seen in MPGN IIIB. Not only C3GN but also non-C3GN was due to mechanisms other than IC deposition as found in postinfectious GN. Consequently, GBM disruption of MPGN IIIA/S was not due to IC deposition.
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Affiliation(s)
- Shiko Honma
- Department of Pathology, School of Medicine, The Jikei University, Tokyo, Japan
| | - Naomi Sato
- Department of Pathology, Graduate School of Medicine, Tohoku University, Sendai, Japan
- Department of Pathology, Iwate Prefectural Central Hospital, Iwate, Japan
| | - Ryoko Sakaguchi
- Department of Pathology, School of Medicine, The Jikei University, Tokyo, Japan
| | - Akinori Hashiguchi
- Department of Pathology, School of Medicine, Keio University, Tokyo, Japan
| | - Noriko Uesugi
- Department of Pathology, Fukuoka University of Medicine, Fukuoka, Japan
| | - Yasuhiro Nakamura
- Faculty of Medicine, Division of Pathology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Hironobu Sasano
- Department of Pathology, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Kensuke Joh
- Department of Pathology, School of Medicine, The Jikei University, Tokyo, Japan.
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Nell D, Wolf R, Podgorny PM, Kuschnereit T, Kuschnereit R, Dabers T, Stracke S, Schmidt T. Complement Activation in Nephrotic Glomerular Diseases. Biomedicines 2024; 12:455. [PMID: 38398059 PMCID: PMC10886869 DOI: 10.3390/biomedicines12020455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/23/2024] [Accepted: 02/09/2024] [Indexed: 02/25/2024] Open
Abstract
The nephrotic syndrome holds significant clinical importance and is characterized by a substantial protein loss in the urine. Damage to the glomerular basement membrane or podocytes frequently underlies renal protein loss. There is an increasing belief in the involvement of the complement system, a part of the innate immune system, in these conditions. Understanding the interactions between the complement system and glomerular structures continually evolves, challenging the traditional view of the blood-urine barrier as a passive filter. Clinical studies suggest that a precise inhibition of the complement system at various points may soon become feasible. However, a thorough understanding of current knowledge is imperative for planning future therapies in nephrotic glomerular diseases such as membranous glomerulopathy, membranoproliferative glomerulonephritis, lupus nephritis, focal segmental glomerulosclerosis, and minimal change disease. This review provides an overview of the complement system, its interactions with glomerular structures, and insights into specific glomerular diseases exhibiting a nephrotic course. Additionally, we explore new diagnostic tools and future therapeutic approaches.
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34
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Sándor N, Schneider AE, Matola AT, Barbai VH, Bencze D, Hammad HH, Papp A, Kövesdi D, Uzonyi B, Józsi M. The human factor H protein family - an update. Front Immunol 2024; 15:1135490. [PMID: 38410512 PMCID: PMC10894998 DOI: 10.3389/fimmu.2024.1135490] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 01/08/2024] [Indexed: 02/28/2024] Open
Abstract
Complement is an ancient and complex network of the immune system and, as such, it plays vital physiological roles, but it is also involved in numerous pathological processes. The proper regulation of the complement system is important to allow its sufficient and targeted activity without deleterious side-effects. Factor H is a major complement regulator, and together with its splice variant factor H-like protein 1 and the five human factor H-related (FHR) proteins, they have been linked to various diseases. The role of factor H in inhibiting complement activation is well studied, but the function of the FHRs is less characterized. Current evidence supports the main role of the FHRs as enhancers of complement activation and opsonization, i.e., counter-balancing the inhibitory effect of factor H. FHRs emerge as soluble pattern recognition molecules and positive regulators of the complement system. In addition, factor H and some of the FHR proteins were shown to modulate the activity of immune cells, a non-canonical function outside the complement cascade. Recent efforts have intensified to study factor H and the FHRs and develop new tools for the distinction, quantification and functional characterization of members of this protein family. Here, we provide an update and overview on the versatile roles of factor H family proteins, what we know about their biological functions in healthy conditions and in diseases.
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Affiliation(s)
- Noémi Sándor
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, Budapest, Hungary
| | | | | | - Veronika H. Barbai
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Dániel Bencze
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Hani Hashim Hammad
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Alexandra Papp
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Dorottya Kövesdi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, Budapest, Hungary
| | - Barbara Uzonyi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, Budapest, Hungary
| | - Mihály Józsi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
- HUN-REN-ELTE Complement Research Group, Hungarian Research Network, Budapest, Hungary
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Gao S, Song H. Integrated comparison of the mRNAome in cartilage, synovium, and macrophages in osteoarthritis. Z Rheumatol 2024; 83:62-70. [PMID: 35178608 DOI: 10.1007/s00393-022-01171-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/21/2022] [Indexed: 11/09/2022]
Abstract
The precise molecular mechanisms associated with osteoarthritis (OA), the most common musculoskeletal disorder, are poorly understood. There are currently no effective treatments to prevent the initiation and progression of the disease. In recent years, the development of mRNAome has made it possible to identify new mechanisms and therapeutic targets. However, the differentially expressed genes screened by different microarrays are not completely the same. In order to avoid this shortcoming, we integrate the different genes from different tissues and data sets, and select the commonly expressed genes for further studies.
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Affiliation(s)
- Siming Gao
- Department of Rheumatology, Beijing Jishuitan Hospital, No. 31, Xin Jie Kou East Street, Xicheng District, 100035, Beijing, China
| | - Hui Song
- Department of Rheumatology, Beijing Jishuitan Hospital, No. 31, Xin Jie Kou East Street, Xicheng District, 100035, Beijing, China.
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Nayak PP, Pradhan P, Pradhan D, Mohapatra N, Raman S, Sahoo P. To interpret and analyze the changing patterns of histology and direct immunofluorescence findings in membranoproliferative glomerulonephritis. INDIAN J PATHOL MICR 2024; 67:80-85. [PMID: 38358193 DOI: 10.4103/ijpm.ijpm_1015_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024] Open
Abstract
Background Membranoproliferative glomerulonephritis has in the recent past been regrouped into immune complex-mediated (ICM MPGN) disease (driven by the classical complement pathway) and complement-mediated (C3GN) disease (driven by the alternative complement pathway) based on pathogenetic role of alternative complement pathway and immunofluorescence deposits. The proposed regrouping lent therapeutic and prognostic support in managing the disease of MPGN. Aims and Objectives The present study is undertaken to study the patterns of MPGN based on histopathological and DIF examination and sub-categorize the cases into mainly complement dominant and immune complex-mediated diseases for better prognostic and therapeutic utility. Materials and Methods This is a prospective observational study carried out in a tertiary care center over a period of 2 yrs. The clinically suspected cases of MPGN were subjected to histopathologic and direct immunofluorescence examination (DIF), and the findings were interpreted in light of complement-mediated and immune complex-mediated MPGN. Results Out of 620 renal biopsies, diagnosis of MPGN was confirmed both on histopathology and DIF in 36 cases accounting for 5.8% of all biopsies. Based on DIF findings, the various groups comprised 20 cases (55.6%) of immune complex deposits, 11 (30.5%) of C3 dominant picture, and 5 (13.9%) of Nil immune deposits. On analysis of the patterns on DIF, 16 cases (80%) of C3 + Ig group and 6 (54.5%) of C3GN group showed predominantly MPGN pattern. Crescentic glomerulonephritis, global glomerulosclerosis, and interstitial fibrosis were markedly observed in C3GN group. Conclusion DIF is of immense prognostic and therapeutic value in managing cases of MPGN.
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Affiliation(s)
- Pragnya P Nayak
- Department of Patholgy, Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
| | - Pranati Pradhan
- Department of Patholgy, Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
| | - Dilleswari Pradhan
- Department of Patholgy, Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
| | - Nachiketa Mohapatra
- Department of Patholgy, Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
| | - Sarojini Raman
- Department of Patholgy, Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
| | - Pranabandhu Sahoo
- Department of Patholgy, Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
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Loganathan L, Jeyaraman J, Muthusamy K. HTNpedia: A Knowledge Base for Hypertension Research. Comb Chem High Throughput Screen 2024; 27:745-753. [PMID: 37202885 DOI: 10.2174/1386207326666230518162439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 03/27/2023] [Accepted: 03/31/2023] [Indexed: 05/20/2023]
Abstract
BACKGROUND Hypertension is notably a serious public health concern due to its high prevalence and strong association with cardiovascular disease and renal failure. It is reported to be the fourth leading disease that leads to death worldwide. OBJECTIVES Currently, there is no active operational knowledge base or database for hypertension or cardiovascular illness. METHODS The primary data source was retrieved from the research outputs obtained from our laboratory team working on hypertension research. We have presented a preliminary dataset and external links to the public repository for detailed analysis to readers. RESULTS As a result, HTNpedia was created to provide information regarding hypertension-related proteins and genes. CONCLUSION The complete webpage is accessible via www.mkarthikeyan.bioinfoau.org/HTNpedia.
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Affiliation(s)
- Lakshmanan Loganathan
- Department of Bioinformatics, Alagappa University, Karaikudi, 630003, Tamil Nadu, India
| | - Jeyakanthan Jeyaraman
- Department of Bioinformatics, Alagappa University, Karaikudi, 630003, Tamil Nadu, India
| | - Karthikeyan Muthusamy
- Department of Bioinformatics, Alagappa University, Karaikudi, 630003, Tamil Nadu, India
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Vivarelli M, Bomback AS, Meier M, Wang Y, Webb NJ, Veldandi UK, Smith RJ, Kavanagh D. Iptacopan in Idiopathic Immune Complex-Mediated Membranoproliferative Glomerulonephritis: Protocol of the APPARENT Multicenter, Randomized Phase 3 Study. Kidney Int Rep 2024; 9:64-72. [PMID: 38312795 PMCID: PMC10831369 DOI: 10.1016/j.ekir.2023.10.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 10/16/2023] [Accepted: 10/23/2023] [Indexed: 02/06/2024] Open
Abstract
Introduction Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) is an ultra-rare, fast-progressing kidney disease that may be idiopathic (primary) or secondary to chronic infection, autoimmune disorders, or monoclonal gammopathies. Dysregulation of the alternative complement pathway is implicated in the pathophysiology of IC-MPGN; and currently, there are no approved targeted treatments. Iptacopan is an oral, highly potent proximal complement inhibitor that specifically binds to factor B and inhibits the alternative pathway (AP). Methods This randomized, double-blind, placebo-controlled phase 3 study (APPARENT; NCT05755386) will evaluate the efficacy and safety of iptacopan in patients with idiopathic (primary) IC-MPGN, enrolling up to 68 patients (minimum of 10 adolescents) aged 12 to 60 years with biopsy-confirmed IC-MPGN, proteinuria ≥1 g/g, and estimated glomerular filtration rate (eGFR) ≥30 ml/min per 1.73 m2. All patients will receive maximally tolerated angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and vaccination against encapsulated bacteria. Patients with any organ transplant, progressive crescentic glomerulonephritis, or kidney biopsy with >50% interstitial fibrosis/tubular atrophy, will be excluded. Patients will be randomized 1:1 to receive either iptacopan 200 mg twice daily (bid) or placebo for 6 months, followed by open-label treatment with iptacopan 200 mg bid for all patients for 6 months. The primary objective of the study is to evaluate the efficacy of iptacopan versus placebo in proteinuria reduction measured as urine protein-to-creatinine ratio (UPCR) (24-h urine) at 6 months. Key secondary end points will assess kidney function measured by eGFR, patients who achieve a proteinuria-eGFR composite end point, and patient-reported fatigue. Conclusion This study will provide evidence toward the efficacy and safety of iptacopan in idiopathic (primary) IC-MPGN.
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Affiliation(s)
- Marina Vivarelli
- Division of Nephrology, Laboratory of Nephrology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Andrew S. Bomback
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Matthias Meier
- Global Drug Development, Novartis Pharma AG, Basel, Switzerland
| | - Yaqin Wang
- Global Drug Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | | | | | - Richard J.H. Smith
- Molecular Otolaryngology and Renal Research Laboratories and the Departments of Internal Medicine and Pediatrics (Divisions of Nephrology), Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
| | - David Kavanagh
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals, National Health Service Foundation Trust, Newcastle upon Tyne, UK
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Zotta F, Diomedi-Camassei F, Gargiulo A, Cappoli A, Emma F, Vivarelli M. Successful treatment with avacopan (CCX168) in a pediatric patient with C3 glomerulonephritis. Pediatr Nephrol 2023; 38:4197-4201. [PMID: 37306717 DOI: 10.1007/s00467-023-06035-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/14/2023] [Accepted: 05/23/2023] [Indexed: 06/13/2023]
Abstract
BACKGROUND C3 glomerulonephritis (C3GN) is a subtype of C3 glomerulopathy (C3G), characterized by dysregulation of the alternative pathway of complement and by dominant C3 by immunofluorescence on the kidney biopsy. There is no approved treatment for patients with C3G. Immunosuppressive drugs as well as biologics have been used with limited success. In recent decades, substantial advances in the understanding of the complement system have led to the development of new complement inhibitors. Avacopan (CCX168) is an orally administered small-molecule C5aR antagonist that blocks the effects of C5a, one of the most potent pro-inflammatory mediators of the complement system. CASE REPORT We describe a child with biopsy-proven C3GN treated with avacopan. She was enrolled in the ACCOLADE double-blind placebo-controlled Phase 2 study (NCT03301467), where during the first 26 weeks she was randomized to receive an avacopan-matching placebo orally twice daily, while in the following 26 weeks, the study was open-label and she received avacopan. After a wash-out period, she was restarted on avacopan through an expanded access program. CONCLUSIONS In this case, use of avacopan in a pediatric patient with C3GN was safe and well tolerated. On avacopan, the patient was able to discontinue mycophenolate mofetil (MMF) while maintaining remission.
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Affiliation(s)
- Federica Zotta
- Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.
| | | | - Antonio Gargiulo
- Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy
| | - Andrea Cappoli
- Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy
| | - Francesco Emma
- Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy
| | - Marina Vivarelli
- Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy
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Wong E, Nester C, Cavero T, Karras A, Le Quintrec M, Lightstone L, Eisenberger U, Soler MJ, Kavanagh D, Daina E, Praga M, Medjeral-Thomas NR, Gäckler A, Garcia-Carro C, Biondani A, Chaperon F, Kulmatycki K, Milojevic J, Webb NJ, Nidamarthy PK, Junge G, Remuzzi G. Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy. Kidney Int Rep 2023; 8:2754-2764. [PMID: 38106570 PMCID: PMC10719607 DOI: 10.1016/j.ekir.2023.09.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/21/2023] [Accepted: 09/11/2023] [Indexed: 12/19/2023] Open
Abstract
Introduction Complement 3 glomerulopathy (C3G) is a rare inflammatory kidney disease mediated by dysregulation of the alternative complement pathway. No targeted therapy exists for this aggressive glomerulonephritis. Efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (measured by complement biomarkers) of iptacopan were assessed in patients with C3G. Methods In this phase 2, multicenter, open-label, single-arm, nonrandomized study, adults with biopsy-proven, native kidney C3G (native cohort) and kidney transplant recipients with C3G recurrence (recurrent kidney transplant [KT] cohort) received iptacopan twice daily (bid) for 84 days (days 1-21: 10-100 mg; days 22-84: 200 mg). The primary end point was the urine protein-to-creatinine ratio (UPCR; native cohort) and the change in the C3 deposit score of kidney biopsy (recurrent KT cohort). The complement pathway measures included Wieslab assay, soluble C5b9, and serum C3 levels. Results A total of 27 patients (16 native cohort and 11 recurrent KT cohort) were enrolled and all completed the study. In the native cohort, UPCR levels decreased by 45% from baseline to week 12 (P = 0.0003). In the recurrent KT cohort, the median C3 deposit score decreased by 2.50 (scale: 0-12) on day 84 versus baseline (P = 0.03). Serum C3 levels were normalized in most patients; complement hyperactivity observed pretreatment was reduced. Severe adverse events (AEs) included post-biopsy hematuria and hyperkalemia. No deaths occurred during the study. Conclusion Iptacopan resulted in statistically significant and clinically important reductions in UPCR and normalization of serum C3 levels in the native cohort and reduced C3 deposit scores in the recurrent KT cohort with favorable safety and tolerability. (ClinicalTrials.gov identifier: NCT03832114).
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Affiliation(s)
- Edwin Wong
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Carla Nester
- The University of Iowa Stead Family Children’s Hospital, Iowa City, Iowa, USA
| | - Teresa Cavero
- Nephrology Department, University Hospital Doce de Octubre, Madrid, Spain
| | - Alexandre Karras
- Department of Nephrology, Hôpital Européen Georges-Pompidou, APHP, Paris, France
| | - Moglie Le Quintrec
- Service de Néphrologie et Transplantation Rénale, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
| | - Liz Lightstone
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, UK
| | - Ute Eisenberger
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Maria Jose Soler
- Nephrology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Research, CSUR National Unit of Expertise for Complex Glomerular Diseases of Spain, Barcelona, Spain
| | - David Kavanagh
- National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
| | - Erica Daina
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Manuel Praga
- Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain
| | - Nicholas R. Medjeral-Thomas
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, UK
| | - Anja Gäckler
- Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Clara Garcia-Carro
- Nephrology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Research, CSUR National Unit of Expertise for Complex Glomerular Diseases of Spain, Barcelona, Spain
| | - Andrea Biondani
- Novartis Institutes for BioMedical Research, Translational Medicine, Novartis AG, Basel, Switzerland
| | - Frederique Chaperon
- Novartis Institutes for BioMedical Research, Translational Medicine, Novartis AG, Basel, Switzerland
| | - Kenneth Kulmatycki
- Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA
| | - Julie Milojevic
- Novartis Institutes for BioMedical Research, Translational Medicine, Novartis AG, Basel, Switzerland
| | - Nicholas J.A. Webb
- Novartis Institutes for BioMedical Research, Translational Medicine, Novartis AG, Basel, Switzerland
| | | | - Guido Junge
- Novartis Institutes for BioMedical Research, Translational Medicine, Novartis AG, Basel, Switzerland
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
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Lafayette RA, Charu V. Expert Discussion on Challenges in C3G Diagnosis: A Podcast Article on Best Practices in Kidney Biopsies. Adv Ther 2023; 40:5557-5566. [PMID: 37751024 PMCID: PMC10611840 DOI: 10.1007/s12325-023-02654-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 08/17/2023] [Indexed: 09/27/2023]
Abstract
Complement 3 glomerulopathy (C3G) is an ultra-rare, progressive kidney disease resulting from dysregulation of the alternative complement pathway. Clinical presentation of C3G is heterogeneous and definitive diagnosis relies on kidney biopsy and immunofluorescence staining. The term C3G encompasses two subgroups, dense deposit disease and C3 glomerulonephritis, distinguished via electron microscopy. In this podcast article, the authors discuss the challenges associated with C3G diagnosis and the central role of kidney biopsy. Using an illustrative case study, key histological observations are described, and best practices are discussed from the perspectives of a nephrologist and a nephropathologist. Podcast Audio (MP4 141866 KB).
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Affiliation(s)
| | - Vivek Charu
- Department of Pathology, Stanford University, Stanford, CA, USA
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Abstract
The complement cascade comprises soluble and cell surface proteins and is an important arm of the innate immune system. Once activated, the complement system rapidly generates large quantities of protein fragments that are potent mediators of inflammatory, vasoactive and metabolic responses. Although complement is crucial to host defence and homeostasis, its inappropriate or uncontrolled activation can also drive tissue injury. For example, the complement system has been known for more than 50 years to be activated by glomerular immune complexes and to contribute to autoimmune kidney disease. Notably, the latest research shows that complement is also activated in kidney diseases that are not traditionally thought of as immune-mediated, including haemolytic-uraemic syndrome, diabetic kidney disease and focal segmental glomerulosclerosis. Several complement-targeted drugs have been approved for the treatment of kidney disease, and additional anti-complement agents are being investigated in clinical trials. These drugs are categorically different from other immunosuppressive agents and target pathological processes that are not effectively inhibited by other classes of immunosuppressants. The development of these new drugs might therefore have considerable benefits in the treatment of kidney disease.
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Affiliation(s)
- Vojtech Petr
- Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Joshua M Thurman
- University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
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Meuleman MS, Vieira-Martins P, El Sissy C, Audard V, Baudouin V, Bertrand D, Bridoux F, Louillet F, Dossier C, Esnault V, Jourde-Chiche N, Karras A, Morin MP, Provot F, Remy P, Ribes D, Rousset-Rouviere C, Servais A, Thervet E, Tricot L, Zaidan M, Wynckel A, Zuber J, Le Quintrec M, Frémeaux-Bacchi V, Chauvet S. Rare Variants in Complement Gene in C3 Glomerulopathy and Immunoglobulin-Mediated Membranoproliferative GN. Clin J Am Soc Nephrol 2023; 18:1435-1445. [PMID: 37615951 PMCID: PMC10637453 DOI: 10.2215/cjn.0000000000000252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 08/17/2023] [Indexed: 08/25/2023]
Abstract
BACKGROUND C3 glomerulopathy and idiopathic immunoglobulin-mediated membranoproliferative GN (Ig-MPGN) are rare complement-mediated kidney diseases. Inherited forms of C3 glomerulopathy/Ig-MPGN are rarely described. METHODS Three hundred ninety-eight patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102) from a national registry were screened for three complement genes: factor H ( CFH ), factor I ( CFI ), and C3 . Patients with rare variant (minor allele frequency <0.1%) were included. Epidemiologic, clinical, and immunologic data at diagnosis and kidney outcomes of patients were retrospectively collected. RESULTS Fifty-three different rare variants, including 30 (57%), 13 (24%), and ten (19%) in CFH , CFI , and C3 variants, were identified in 66/398 (17%) patients. Thirty-eight (72%) variants were classified as pathogenic, including 20/30 (66%) and 11/13 (84%) variants in CFH and CFI , respectively, impairing synthesis of factor H or factor I regulators. Fifteen of 53 (27%) variants were of unknown significance. At diagnosis, 69% of patients were adult (median age of 31 years). With the exception of biologic stigma of thrombotic microangiopathy, which was more frequent in patients with CFI variants (5/14 [36%] versus 1/37 [3%] and 0% in the CFH group and C3 group, respectively, P < 0.001), the clinical and histologic features were similar among the three variants groups. The kidney outcome was poor regardless of the age at onset and treatment received. Sixty-five percent (43/66) of patients with rare variant reach kidney failure after a median delay of 41 (19-104) months, compared with 28% (55/195) after a median delay of 34 (12-143) months in the nonvariant group. Among 36 patients who received a kidney transplant, 2-year recurrence was frequent, occurring in 39% (12/31), without difference between variant groups, and led to graft failure in three cases. CONCLUSIONS In our cohort, 17% of C3 glomerulopathy/Ig-MPGN cases were associated with rare variants in the CFH , CFI , or C3 genes. In most cases, a quantitative deficiency in factor H or factor I was identified. The presence of a rare variant was associated with poor kidney survival. PODCAST This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_11_08_CJN0000000000000252.mp3.
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Affiliation(s)
- Marie Sophie Meuleman
- Team “Inflammation, Complement and Cancer,” INSERM UMRS1138, Centre de Recherche des Cordeliers, Paris, France
| | - Paula Vieira-Martins
- Department of Immunology Biology, Assistance Publique-Hôpitaux de Paris, European Hospital Georges Pompidou, Paris, France
| | - Carine El Sissy
- Team “Inflammation, Complement and Cancer,” INSERM UMRS1138, Centre de Recherche des Cordeliers, Paris, France
- Department of Immunology Biology, Assistance Publique-Hôpitaux de Paris, European Hospital Georges Pompidou, Paris, France
| | - Vincent Audard
- Department of Nephrology and Transplantation, Assistance Publique-Hôpitaux de Paris, Henri-Mondor Hospital, Créteil, France
- INSERM U955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil, France
| | - Véronique Baudouin
- Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Paris, France
| | | | - Frank Bridoux
- Department of Nephrology, Poitiers University Hospital, Poitiers, France
| | | | - Claire Dossier
- Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Paris, France
| | - Vincent Esnault
- Department of Nephrology, Nice University Hospital, Nice, France
| | - Noémie Jourde-Chiche
- Department of Nephrology, Assistance Publique-Hôpitaux de Marseille, CHU Conception, Marseille, France
- INSERM, INRAE, C2VN, Aix-Marseille University, Marseille, France
| | - Alexandre Karras
- Department of Nephrology, Assistance Publique-Hôpitaux de Paris, European Hospital Georges Pompidou, Paris, France
| | | | - François Provot
- Department of Nephrology, Lille University Hospital, Lille, France
| | - Philippe Remy
- Department of Nephrology and Transplantation, Assistance Publique-Hôpitaux de Paris, Henri-Mondor Hospital, Créteil, France
| | - David Ribes
- Department of Nephrology, Toulouse University Hospital, Toulouse, France
| | - Caroline Rousset-Rouviere
- Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Marseille, Timone Hospital, Marseille, France
| | - Aude Servais
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Paris, Necker Hospital, Paris, France
| | - Eric Thervet
- Department of Nephrology, Assistance Publique-Hôpitaux de Paris, European Hospital Georges Pompidou, Paris, France
| | - Leila Tricot
- Department of Nephrology, Foch Hospital, Suresnes, France
| | - Mohamad Zaidan
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Paris, Bicetre Hospital, Le Kremlin-Bicêtre, France
| | - Alain Wynckel
- Department of Nephrology, Reims University Hospital, Reims, France
| | - Julien Zuber
- Department of Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Paris, Necker Hospital, Paris, France
| | - Moglie Le Quintrec
- Department of Nephrology, Montpellier University Hospital, Montpellier, France
| | - Véronique Frémeaux-Bacchi
- Team “Inflammation, Complement and Cancer,” INSERM UMRS1138, Centre de Recherche des Cordeliers, Paris, France
- Department of Immunology Biology, Assistance Publique-Hôpitaux de Paris, European Hospital Georges Pompidou, Paris, France
| | - Sophie Chauvet
- Team “Inflammation, Complement and Cancer,” INSERM UMRS1138, Centre de Recherche des Cordeliers, Paris, France
- Department of Nephrology, Assistance Publique-Hôpitaux de Paris, European Hospital Georges Pompidou, Paris, France
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Dixon BP, Greenbaum LA, Huang L, Rajan S, Ke C, Zhang Y, Li L. Clinical Safety and Efficacy of Pegcetacoplan in a Phase 2 Study of Patients with C3 Glomerulopathy and Other Complement-Mediated Glomerular Diseases. Kidney Int Rep 2023; 8:2284-2293. [PMID: 38025230 PMCID: PMC10658235 DOI: 10.1016/j.ekir.2023.08.033] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/15/2023] [Accepted: 08/21/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Dysregulated complement activation is likely the primary driver of disease in C3 glomerulopathy (C3G) and contributes to other complement-mediated diseases, including immunoglobulin A nephropathy (IgAN), lupus nephritis (LN), and primary membranous nephropathy (PMN). No complement inhibitors are proven to halt disease progression in these diseases. Pegcetacoplan, a targeted C3 and C3b inhibitor, may mitigate complement-mediated kidney damage in C3G and other glomerular diseases in which complement may have a pathogenic role. Methods This open-label, phase 2, 48-week study evaluated the preliminary efficacy and safety of subcutaneous pegcetacoplan for patients with complement-mediated glomerular diseases. The primary end point was proteinuria reduction, measured as 24-hour urine protein-to-creatinine ratio. Secondary end points included remission status, changes in estimated glomerular filtration rate (eGFR), and pharmacodynamic biomarkers. Treatment-emergent adverse events (TEAEs) were monitored. Results Efficacy results for the C3G cohort are reported herein, along with safety results for the study population. In the C3G cohort, mean proteinuria reduction from baseline to week 48 was 50.9% in the intent-to-treat (ITT) population (n = 7) and 65.4% in the per-protocol (PP) population (n = 4). Mean serum albumin normalized and mean eGFR was stable over 48 weeks. Mean serum C3 levels increased 6-fold and mean soluble C5b-9 levels decreased by 57.3% at week 48. The most common adverse events (AEs) were upper respiratory tract infection, injection site erythema, nausea, and headache. No meningitis or sepsis cases were reported, and no serious treatment-related AEs were observed. Conclusion Pegcetacoplan may provide therapeutic benefit for C3G and has a favorable safety profile across the 4 glomerular diseases studied.
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Affiliation(s)
- Bradley P. Dixon
- Renal Section, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Larry A. Greenbaum
- Emory University and Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Liwei Huang
- Tidewater Kidney Specialists, Inc, Chesapeake, Virginia, USA
| | - Sandeep Rajan
- Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Chunlei Ke
- Apellis Pharmaceuticals, Inc., Waltham, Massachusetts, USA
| | - Yiwei Zhang
- Apellis Pharmaceuticals, Inc., Waltham, Massachusetts, USA
| | - Li Li
- Apellis Pharmaceuticals, Inc., Waltham, Massachusetts, USA
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Shekarchian F, Hosseini SM, Khazaei S. Hypertensive retinopathy and Purtscher-like retinopathy in a child with complement 3 glomerulopathy. J AAPOS 2023; 27:312-314. [PMID: 37717617 DOI: 10.1016/j.jaapos.2023.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Revised: 06/19/2023] [Accepted: 07/03/2023] [Indexed: 09/19/2023]
Abstract
We report the case of a 15-year-old boy with hypertensive retinopathy and Purtscher-like retinopathy eventually diagnosed with complement 3 glomerulopathy (C3G). The patient presented with bilateral severe painless visual loss and posterior pole cotton wool spots, optic disk and macular edema, and macular star-shaped hard exudate depositions, arterial narrowing, and venous tortuosity, indicative of hypertensive retinopathy (with an initial blood pressure of 210/130 mm Hg) and Purtscher-like retinopathy. He was subsequently diagnosed with C3G based on results of a kidney biopsy. There was a mild visual improvement on follow-up examination, and optic disk swelling and subretinal fluid and cotton wool spots resolved.
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Affiliation(s)
- Farid Shekarchian
- Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Sahel Khazaei
- Eye Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Boi R, Ebefors K, Nyström J. The role of the mesangium in glomerular function. Acta Physiol (Oxf) 2023; 239:e14045. [PMID: 37658606 DOI: 10.1111/apha.14045] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/12/2023] [Accepted: 08/01/2023] [Indexed: 09/03/2023]
Abstract
When discussing glomerular function, one cell type is often left out, the mesangial cell (MC), probably since it is not a part of the filtration barrier per se. The MCs are instead found between the glomerular capillaries, embedded in their mesangial matrix. They are in direct contact with the endothelial cells and in close contact with the podocytes and together they form the glomerulus. The MCs can produce and react to a multitude of growth factors, cytokines, and other signaling molecules and are in the perfect position to be a central hub for crosstalk communication between the cells in the glomerulus. In certain glomerular diseases, for example, in diabetic kidney disease or IgA nephropathy, the MCs become activated resulting in mesangial expansion. The expansion is normally due to matrix expansion in combination with either proliferation or hypertrophy. With time, this expansion can lead to fibrosis and decreased glomerular function. In addition, signs of complement activation are often seen in biopsies from patients with glomerular disease affecting the mesangium. This review aims to give a better understanding of the MCs in health and disease and their role in glomerular crosstalk and inflammation.
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Affiliation(s)
- Roberto Boi
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Kerstin Ebefors
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jenny Nyström
- Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Rydberg V, Aradottir SS, Kristoffersson AC, Svitacheva N, Karpman D. Genetic investigation of Nordic patients with complement-mediated kidney diseases. Front Immunol 2023; 14:1254759. [PMID: 37744338 PMCID: PMC10513385 DOI: 10.3389/fimmu.2023.1254759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 08/21/2023] [Indexed: 09/26/2023] Open
Abstract
Background Complement activation in atypical hemolytic uremic syndrome (aHUS), C3 glomerulonephropathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) may be associated with rare genetic variants. Here we describe gene variants in the Swedish and Norwegian populations. Methods Patients with these diagnoses (N=141) were referred for genetic screening. Sanger or next-generation sequencing were performed to identify genetic variants in 16 genes associated with these conditions. Nonsynonymous genetic variants are described when they have a minor allele frequency of <1% or were previously reported as being disease-associated. Results In patients with aHUS (n=94, one also had IC-MPGN) 68 different genetic variants or deletions were identified in 60 patients, of which 18 were novel. Thirty-two patients had more than one genetic variant. In patients with C3G (n=40) 29 genetic variants, deletions or duplications were identified in 15 patients, of which 9 were novel. Eight patients had more than one variant. In patients with IC-MPGN (n=7) five genetic variants were identified in five patients. Factor H variants were the most frequent in aHUS and C3 variants in C3G. Seventeen variants occurred in more than one condition. Conclusion Genetic screening of patients with aHUS, C3G and IC-MPGN is of paramount importance for diagnostics and treatment. In this study, we describe genetic assessment of Nordic patients in which 26 novel variants were found.
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Affiliation(s)
| | | | | | | | - Diana Karpman
- Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund, Sweden
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Chabannes M, Rabant M, El Sissy C, Dragon-Durey MA, Vieira Martins P, Meuleman MS, Karras A, Buob D, Bridoux F, Daugas E, Audard V, Caillard S, Olagne J, Kandel C, Ferlicot S, Philipponnet C, Crepin T, Thervet E, Ducloux D, Frémeaux-Bacchi V, Chauvet S. C3 Glomerulopathy With Concurrent Thrombotic Microangiopathy: Clinical and Immunological Features. Am J Kidney Dis 2023; 82:279-289. [PMID: 37061020 DOI: 10.1053/j.ajkd.2022.12.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 12/31/2022] [Indexed: 04/17/2023]
Abstract
RATIONALE & OBJECTIVE C3 glomerulopathy (C3GN) and atypical hemolytic uremic syndrome (aHUS) are 2 distinct rare kidney diseases caused by dysregulation of the alternative complement pathway. Patients with C3GN and concurrent kidney lesions of thrombotic microangiopathy (TMA) have been rarely reported. We characterized the clinical features and underlying immunological abnormalities in these patients. STUDY DESIGN Case series. SETTING & PARTICIPANTS Patients with C3GN and concomitant TMA lesions on biopsy registered from 2009 to 2019 in the French National Registry of C3GN. FINDINGS Among 278 registered patients with C3GN, 16 (6%) had biopsy-proven glomerular and/or vascular TMA lesions. Their median age at diagnosis was 39 years (range, 7-76), and 59% were female. Fourteen of the 16 patients (88%) had an estimated glomerular filtration rate of<30mL/min/1.73m2 and 3 of 16 (19%) required dialysis. Twelve of the 14 evaluated patients (86%) showed evidence of mechanical hemolysis. Fifty percent of the patients had low C3 levels. Six of the 14 evaluated patients had a rare variant in complement genes, and 4 of the 16 patients (25%) had monoclonal gammopathy. Among the 16 patients, 10 (63%) received eculizumab, 5 (31%) received immunosuppressive therapy, and 4 (25%) received clone-targeted chemotherapy. Median kidney survival was 49 months. LIMITATIONS Small retrospective case series with a limited number of biopsies including electron microscopy. CONCLUSIONS Concomitant C3GN and TMA is extremely rare and is associated with poor kidney outcomes. Genetic or acquired abnormalities of the alternative complement pathway are common as is the presence of monoclonal gammopathy, which may inform the selection of treatment approaches.
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Affiliation(s)
- Melchior Chabannes
- Department of Nephrology, Dialysis and Renal Transplantation, University Hospital, Besançon
| | - Marion Rabant
- Department of Pathology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris; Université de Paris Cité, Paris, France
| | - Carine El Sissy
- Department of Biological Immunology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris
| | - Marie-Agnès Dragon-Durey
- Department of Biological Immunology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris; INSERM UMRS 1138, Cordelier Research Center, Paris; Université de Paris Cité, Paris, France
| | - Paula Vieira Martins
- Department of Biological Immunology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris
| | - Marie Sophie Meuleman
- INSERM UMRS 1138, Cordelier Research Center, Paris; Université de Paris Cité, Paris, France
| | - Alexandre Karras
- Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris
| | - David Buob
- Department of Pathology, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris
| | - Frank Bridoux
- Department of Nephrology, Dialysis and Renal Transplantation, University Hospital, Poitiers
| | - Eric Daugas
- Department of Nephrology, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris
| | - Vincent Audard
- Department of Nephrology and Transplantation, Henri Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, Créteil; Univ Paris Est Creteil, INSERM, IMRB, Créteil, France
| | - Sophie Caillard
- Department of Nephrology and Transplantation, University Hospital, Strasbourg
| | - Jérôme Olagne
- Department of Pathology, University Hospital, Strasbourg
| | | | - Sophie Ferlicot
- Department of Pathology, Hôpital Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre
| | | | - Thomas Crepin
- Department of Nephrology, Dialysis and Renal Transplantation, University Hospital, Besançon
| | - Eric Thervet
- INSERM UMRS 1138, Cordelier Research Center, Paris
| | - Didier Ducloux
- Department of Nephrology, Dialysis and Renal Transplantation, University Hospital, Besançon
| | - Véronique Frémeaux-Bacchi
- Department of Biological Immunology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris
| | - Sophie Chauvet
- Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris; INSERM UMRS 1138, Cordelier Research Center, Paris; Université de Paris Cité, Paris, France.
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Zanchi C, Locatelli M, Corna D, Cerullo D, Fishilevich E, Desai D, Rottoli D, Donadelli R, Noris M, Zoja C, Remuzzi G, Benigni A. Liver factor B silencing to cure C3 glomerulopathy: Evidence from a mouse model of complement dysregulation. Mol Immunol 2023; 161:25-32. [PMID: 37481826 DOI: 10.1016/j.molimm.2023.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/28/2023] [Accepted: 07/18/2023] [Indexed: 07/25/2023]
Abstract
Uncontrolled activation of the alternative pathway (AP) of complement, due to genetic and/or acquired defects, plays a primary pathogenetic role in C3 glomerulopathy (C3G), a rare and heterogeneous disease characterised by predominant C3 fragment deposition within the glomerulus, as well as glomerular damage. There are currently no approved disease-specific treatments for C3G, but new drugs that directly counteract AP dysregulation, targeting components of the pathway, have opened promising new perspectives for managing the disease. Complement factor B (FB), which is primarily synthesised by hepatocytes, is a key component of the AP, as it drives the central amplification loop of the complement system. In this study we used a GalNAc (N-Acetylgalactosamine)-conjugated siRNA to selectively target and suppress liver FB expression in two mouse models characterised by the complete (Cfh-/- mice) or partial (Cfh+/-) loss of function of complement factor H (FH). Homozygous deletion of FH induced a severe C3G phenotype, with strong dysregulation of the AP of complement, glomerular C3 deposition and almost complete C3 consumption. Mice with a heterozygous deletion of FH had intermediate C3 levels and exhibited slower disease progression, resembling human C3G more closely. Here we showed that FB siRNA treatment did not improve serum C3 levels, nor limit glomerular C3 deposition in Cfh-/- mice, while it did normalise circulating C3 levels, reduce glomerular C3 deposits, and limit mesangial electron-dense deposits in Cfh+/- mice. The present data provide important insights into the potential benefits and limitations of FB-targeted inhibition strategies and suggest RNA interference-mediated FB silencing in the liver as a possible therapeutic approach for treating C3G patients with FH haploinsufficiency.
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Affiliation(s)
- Cristina Zanchi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Monica Locatelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Daniela Corna
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Domenico Cerullo
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | | | - Dhruv Desai
- Alnylam Pharmaceuticals Inc., Boston, MA, United States
| | - Daniela Rottoli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Roberta Donadelli
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Marina Noris
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Carlamaria Zoja
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori Science and Technology Park Kilometro Rosso, Bergamo, Italy
| | - Ariela Benigni
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Centro Anna Maria Astori Science and Technology Park Kilometro Rosso, Bergamo, Italy.
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Hallam TM, Sharp SJ, Andreadi A, Kavanagh D. Complement factor I: Regulatory nexus, driver of immunopathology, and therapeutic. Immunobiology 2023; 228:152410. [PMID: 37478687 DOI: 10.1016/j.imbio.2023.152410] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/23/2023] [Accepted: 06/01/2023] [Indexed: 07/23/2023]
Abstract
Complement factor I (FI) is the nexus for classical, lectin and alternative pathway complement regulation. FI is an 88 kDa plasma protein that circulates in an inactive configuration until it forms a trimolecular complex with its cofactor and substrate whereupon a structural reorganization allows the catalytic triad to cleave its substrates, C3b and C4b. In keeping with its role as the master complement regulatory enzyme, deficiency has been linked to immunopathology. In the setting of complete FI deficiency, a consumptive C3 deficiency results in recurrent infections with encapsulated microorganisms. Aseptic cerebral inflammation and vasculitic presentations are also less commonly observed. Heterozygous mutations in the factor I gene (CFI) have been demonstrated to be enriched in atypical haemolytic uraemic syndrome, albeit with a very low penetrance. Haploinsufficiency of CFI has also been associated with decreased retinal thickness and is a strong risk factor for the development of age-related macular degeneration. Supplementation of FI using plasma purified or recombinant protein has long been postulated, however, technical difficulties prevented progression into clinical trials. It is only using gene therapy that CFI supplementation has reached the clinic with GT005 in phase I/II clinical trials for geographic atrophy.
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Affiliation(s)
- T M Hallam
- Gyroscope Therapeutics Limited, A Novartis Company, Rolling Stock Yard, London N7 9AS, UK; Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK; National Renal Complement Therapeutics Centre, Building 26, Royal Victoria Infirmary, UK
| | - S J Sharp
- Gyroscope Therapeutics Limited, A Novartis Company, Rolling Stock Yard, London N7 9AS, UK
| | - A Andreadi
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK; National Renal Complement Therapeutics Centre, Building 26, Royal Victoria Infirmary, UK
| | - D Kavanagh
- Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK; National Renal Complement Therapeutics Centre, Building 26, Royal Victoria Infirmary, UK; NIHR Newcastle Biomedical Research Centre, Biomedical Research Building, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK.
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