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1
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Huang J, Zhu H, Li S, Qiu J, Yang H, Zheng F, Luo Z, Yan Q, Liu F, Yin L, Tang D, Dai Y. Proteomic Insights into IgA Nephropathy: A Comprehensive Analysis of Differentially Expressed Proteins in the Kidney. ACS OMEGA 2025; 10:17208-17220. [PMID: 40352523 PMCID: PMC12059920 DOI: 10.1021/acsomega.4c07827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 04/10/2025] [Accepted: 04/14/2025] [Indexed: 05/14/2025]
Abstract
IgA nephropathy represents a significant challenge in nephrology research, and an understanding of its underlying molecular mechanisms is crucial. In this study, we conducted a comprehensive proteomic investigation of IgA nephropathy utilizing microdissection techniques combined with data-independent acquisition technology. Our analysis focused on differentially expressed proteins in the glomeruli, interstitium, and tubules of the kidney. Functional enrichment analysis revealed distinct pathway enrichment patterns, with fatty acid synthesis predominating in the glomerulus and complement and coagulation pathways predominantly enriched in the tubules. These pathway enrichments suggest potential key contributors to the pathogenesis of IgA nephropathy. Furthermore, our study identified ATP1B1 and COX4I1 in the glomerulus and SLC22A13 in the tubules as promising diagnostic markers for the disease. Meanwhile, C4A and APEX1 proteins were identified as valuable biomarkers for assessing disease progression. This research could provide valuable insights into the proteomic alterations associated with IgA nephropathy and offer potential targets for further therapeutic exploration.
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Affiliation(s)
- Jingxian Huang
- Institute
of Kidney Disease and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Hongguo Zhu
- Institute
of Kidney Disease and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
- Comprehensive
Health Industry Research Center, Taizhou Research Institute, Southern University of Science and Technology, Taizhou 317000, China
| | - Shanshan Li
- Clinical
Medical Research Center, The Second Clinical
Medical College, Jinan University, Shenzhen People’ s Hospital, Shenzhen 518020, China
| | - Jing Qiu
- Clinical
Medical Research Center, The Second Clinical
Medical College, Jinan University, Shenzhen People’ s Hospital, Shenzhen 518020, China
| | - Hougang Yang
- Comprehensive
Health Industry Research Center, Taizhou Research Institute, Southern University of Science and Technology, Taizhou 317000, China
| | - Fengping Zheng
- Institute
of Kidney Disease and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
- Department
of Organ Transplantation, The 924th Hospital
of the Chinese People’s Liberation Army Joint Logistic Support
Force, Guilin 541002, China
| | - Zhifeng Luo
- Institute
of Kidney Disease and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
- Department
of Organ Transplantation, The 924th Hospital
of the Chinese People’s Liberation Army Joint Logistic Support
Force, Guilin 541002, China
| | - Qiang Yan
- Department
of Organ Transplantation, The 924th Hospital
of the Chinese People’s Liberation Army Joint Logistic Support
Force, Guilin 541002, China
| | - Fanna Liu
- Institute
of Kidney Disease and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Lianghong Yin
- Institute
of Kidney Disease and Blood Purification, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China
| | - Donge Tang
- Clinical
Medical Research Center, The Second Clinical
Medical College, Jinan University, Shenzhen People’ s Hospital, Shenzhen 518020, China
| | - Yong Dai
- Clinical
Medical Research Center, The Second Clinical
Medical College, Jinan University, Shenzhen People’ s Hospital, Shenzhen 518020, China
- Department
of Organ Transplantation, The 924th Hospital
of the Chinese People’s Liberation Army Joint Logistic Support
Force, Guilin 541002, China
- School
of Medicine, The First Affiliated Hospital,
Anhui University of Science and Technology, Huainan 232001, China
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Lafayette RA, Charu V, Glassock RJ. Expert Discussion on Immune Complex-Mediated Membranoproliferative Glomerulonephritis: Challenges and Considerations. Adv Ther 2025; 42:2003-2014. [PMID: 40146368 PMCID: PMC12006263 DOI: 10.1007/s12325-025-03167-x] [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: 11/29/2024] [Accepted: 03/04/2025] [Indexed: 03/28/2025]
Abstract
Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) is a rare pattern of kidney injury and a progressive nephropathy characterized by the glomerular deposition of immune complexes and complement proteins. The IC-MPGN pattern of injury exhibits a membranoproliferative glomerulonephritis appearance by light microscopy and occurs secondary to various conditions or, more rarely, idiopathically, when no underlying etiology can be determined. Kidney biopsy is the only method for identifying IC-MPGN, distinguishing between IC-MPGN and complement 3 glomerulopathy (C3G), and for providing critical pathologic insights that guide further clinical evaluation for underlying etiologies and inform patient management. Given the progressive nature of IC-MPGN, it is crucial to identify patients early and to define the underlying pathophysiology for timely and appropriate treatment. However, several challenges remain in the accurate interpretation of kidney biopsy specimens and the effective treatment of idiopathic disease. In this commentary, two nephrologists and a nephropathologist review best practices in the clinical and histopathologic evaluation of IC-MPGN and discuss the central role of kidney biopsy in the differentiation of IC-MPGN and C3G. The challenges and considerations discussed are explored through an illustrative case of idiopathic disease, drawn from the authors' clinical experiences. Finally, remaining unmet needs are highlighted, and future perspectives on targeted treatments under investigation for patients with idiopathic IC-MPGN are provided.
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Affiliation(s)
| | - Vivek Charu
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Richard J Glassock
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- , 3329 Bahia Blanca East, Unit B, Laguna Woods, CA, 92637, USA.
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3
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Nakamura J, Yamamoto T, Takabatake Y, Namba-Hamano T, Takahashi A, Matsuda J, Minami S, Sakai S, Yonishi H, Maeda S, Matsui S, Kawai H, Matsui I, Yamamuro T, Edahiro R, Takashima S, Takasawa A, Okada Y, Yoshimori T, Ballabio A, Isaka Y. Age-related TFEB downregulation in proximal tubules causes systemic metabolic disorders and occasional apolipoprotein A4-related amyloidosis. JCI Insight 2024; 10:e184451. [PMID: 39699959 PMCID: PMC11948592 DOI: 10.1172/jci.insight.184451] [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: 07/02/2024] [Accepted: 12/16/2024] [Indexed: 12/21/2024] Open
Abstract
With the aging of society, the incidence of chronic kidney disease (CKD), a common cause of death, has been increasing. Transcription factor EB (TFEB), the master transcriptional regulator of the autophagy/lysosomal pathway, is regarded as a promising candidate for preventing various age-related diseases. However, whether TFEB in the proximal tubules plays a significant role in elderly patients with CKD remains unknown. First, we found that nuclear TFEB localization in proximal tubular epithelial cells (PTECs) declined with age in both mice and humans. Next, we generated PTEC-specific Tfeb-deficient mice and bred them for up to 24 months. We found that TFEB deficiency in the proximal tubules caused metabolic disorders and occasionally led to apolipoprotein A4 (APOA4) amyloidosis. Supporting this result, we identified markedly decreased nuclear TFEB localization in the proximal tubules of elderly patients with APOA4 amyloidosis. The metabolic disturbances were accompanied by mitochondrial dysfunction due to transcriptional changes involved in fatty acid oxidation and oxidative phosphorylation pathways, as well as decreased mitochondrial clearance. This decreased clearance was reflected by the accumulation of mitochondria-lysosome-related organelles, which depended on lysosomal function. These results shed light on the presumptive mechanisms of APOA4 amyloidosis pathogenesis and provide a therapeutic strategy for CKD-related metabolic disorders and APOA4 amyloidosis.
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Affiliation(s)
- Jun Nakamura
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takeshi Yamamoto
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yoshitsugu Takabatake
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tomoko Namba-Hamano
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Takahashi
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Jun Matsuda
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Satoshi Minami
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shinsuke Sakai
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Yonishi
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shihomi Maeda
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Sho Matsui
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hideaki Kawai
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Isao Matsui
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tadashi Yamamuro
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Ryuya Edahiro
- Department of Statistical Genetics and
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
- Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Seiji Takashima
- Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Akira Takasawa
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yukinori Okada
- Department of Statistical Genetics and
- Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe) and
- Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Suita, Japan
- Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Tamotsu Yoshimori
- Health Promotion System Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Andrea Ballabio
- Telethon Institute of Genetics and Medicine (TIGEM), Via Campi Flegrei 34, Pozzuoli, Naples, Italy
- Medical Genetics Unit, Department of Medical and Translational Science, Federico II University, Via Pansini 5, Naples, Italy
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
- Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, USA
| | - Yoshitaka Isaka
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
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4
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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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5
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Wendt R, Sobhani A, Diefenhardt P, Trappe M, Völker LA. An Updated Comprehensive Review on Diseases Associated with Nephrotic Syndromes. Biomedicines 2024; 12:2259. [PMID: 39457572 PMCID: PMC11504437 DOI: 10.3390/biomedicines12102259] [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: 09/06/2024] [Revised: 09/27/2024] [Accepted: 10/01/2024] [Indexed: 10/28/2024] Open
Abstract
There have been exciting advances in our knowledge of primary glomerular diseases and nephrotic syndromes in recent years. Beyond the histological pattern from renal biopsy, more precise phenotyping of the diseases and the use of modern nephrogenetics helps to improve treatment decisions and sometimes also avoid unnecessary exposure to potentially toxic immunosuppression. New biomarkers have led to easier and more accurate diagnoses and more targeted therapeutic decisions. The treatment landscape is becoming wider with a pipeline of promising new therapeutic agents with more sophisticated approaches. This review focuses on all aspects of entities that are associated with nephrotic syndromes with updated information on recent advances in each field. This includes podocytopathies (focal segmental glomerulosclerosis and minimal-change disease), membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, fibrillary glomerulonephritis, amyloidosis, and monoclonal gammopathy of renal significance in the context of the nephrotic syndrome, but also renal involvement in systemic diseases, diabetic nephropathy, and drugs that are associated with nephrotic syndromes.
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Affiliation(s)
- Ralph Wendt
- Department of Nephrology, Hospital St. Georg Leipzig, Delitzscher Str. 141, 04129 Leipzig, Germany
| | - Alina Sobhani
- Department II of Internal Medicine, Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (P.D.); (M.T.); (L.A.V.)
| | - Paul Diefenhardt
- Department II of Internal Medicine, Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (P.D.); (M.T.); (L.A.V.)
- Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases, 50923 Cologne, Germany
| | - Moritz Trappe
- Department II of Internal Medicine, Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (P.D.); (M.T.); (L.A.V.)
| | - Linus Alexander Völker
- Department II of Internal Medicine, Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (A.S.); (P.D.); (M.T.); (L.A.V.)
- Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases, 50923 Cologne, Germany
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6
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Schmidt IM, Surapaneni AL, Zhao R, Upadhyay D, Yeo WJ, Schlosser P, Huynh C, Srivastava A, Palsson R, Kim T, Stillman IE, Barwinska D, Barasch J, Eadon MT, El-Achkar TM, Henderson J, Moledina DG, Rosas SE, Claudel SE, Verma A, Wen Y, Lindenmayer M, Huber TB, Parikh SV, Shapiro JP, Rovin BH, Stanaway IB, Sathe NA, Bhatraju PK, Coresh J, Rhee EP, Grams ME, Waikar SS. Plasma proteomics of acute tubular injury. Nat Commun 2024; 15:7368. [PMID: 39191768 PMCID: PMC11349760 DOI: 10.1038/s41467-024-51304-x] [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: 02/13/2024] [Accepted: 08/05/2024] [Indexed: 08/29/2024] Open
Abstract
The kidney tubules constitute two-thirds of the cells of the kidney and account for the majority of the organ's metabolic energy expenditure. Acute tubular injury (ATI) is observed across various types of kidney diseases and may significantly contribute to progression to kidney failure. Non-invasive biomarkers of ATI may allow for early detection and drug development. Using the SomaScan proteomics platform on 434 patients with biopsy-confirmed kidney disease, we here identify plasma biomarkers associated with ATI severity. We employ regional transcriptomics and proteomics, single-cell RNA sequencing, and pathway analysis to explore biomarker protein and gene expression and enriched biological pathways. Additionally, we examine ATI biomarker associations with acute kidney injury (AKI) in the Kidney Precision Medicine Project (KPMP) (n = 44), the Atherosclerosis Risk in Communities (ARIC) study (n = 4610), and the COVID-19 Host Response and Clinical Outcomes (CHROME) study (n = 268). Our findings indicate 156 plasma proteins significantly linked to ATI with osteopontin, macrophage mannose receptor 1, and tenascin C showing the strongest associations. Pathway analysis highlight immune regulation and organelle stress responses in ATI pathogenesis.
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Affiliation(s)
- Insa M Schmidt
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA.
- Section of Nephrology, Boston Medical Center, Boston, MA, USA.
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Aditya L Surapaneni
- Department of Medicine, New York University Langone School of Medicine, New York, NY, USA
| | - Runqi Zhao
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
- Section of Nephrology, Boston Medical Center, Boston, MA, USA
| | - Dhairya Upadhyay
- Department of Medicine, New York University Langone School of Medicine, New York, NY, USA
| | - Wan-Jin Yeo
- Department of Medicine, New York University Langone School of Medicine, New York, NY, USA
| | - Pascal Schlosser
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany
- Centre for Integrative Biological Signaling Studies (CIBSS), University of Freiburg, Freiburg, Germany
| | - Courtney Huynh
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
- Section of Nephrology, Boston Medical Center, Boston, MA, USA
| | - Anand Srivastava
- Division of Nephrology, University of Illinois Chicago, Chicago, IL, USA
| | - Ragnar Palsson
- Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA
| | - Taesoo Kim
- Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA
| | - Isaac E Stillman
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daria Barwinska
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jonathan Barasch
- Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA
| | - Michael T Eadon
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tarek M El-Achkar
- Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Joel Henderson
- Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - Dennis G Moledina
- Department of Internal Medicine, Section of Nephrology, Yale School of Medicine, New Haven, CT, USA
| | - Sylvia E Rosas
- Kidney and Hypertension Unit, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Sophie E Claudel
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
- Section of Nephrology, Boston Medical Center, Boston, MA, USA
| | - Ashish Verma
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
- Section of Nephrology, Boston Medical Center, Boston, MA, USA
| | - Yumeng Wen
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Maja Lindenmayer
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tobias B Huber
- Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samir V Parikh
- Division of Nephrology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - John P Shapiro
- Division of Nephrology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Brad H Rovin
- Division of Nephrology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Ian B Stanaway
- Kidney Research Institute, Division of Nephrology, University of Washington School of Medicine, Seattle, WA, USA
| | - Neha A Sathe
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Pavan K Bhatraju
- Kidney Research Institute, Division of Nephrology, University of Washington School of Medicine, Seattle, WA, USA
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Josef Coresh
- Department of Medicine, New York University Langone School of Medicine, New York, NY, USA
| | - Eugene P Rhee
- Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA
| | - Morgan E Grams
- Department of Medicine, New York University Langone School of Medicine, New York, NY, USA
| | - Sushrut S Waikar
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
- Section of Nephrology, Boston Medical Center, Boston, MA, USA
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7
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Meuleman MS, Petitprez F, Pickering MC, Le Quintrec M, Artero MR, Duval A, Rabant M, Gilmore A, Boyer O, Hogan J, Servais A, Provot F, Gnemmi V, Eloudzeri M, Grunenwald A, Buob D, Boffa JJ, Moktefi A, Audard V, Goujon JM, Bridoux F, Thervet E, Karras A, Roumenina LT, Frémeaux Bacchi V, Duong Van Huyen JP, Chauvet S. Complement Terminal Pathway Activation and Intrarenal Immune Response in C3 Glomerulopathy. J Am Soc Nephrol 2024; 35:1034-1044. [PMID: 38709564 PMCID: PMC11377803 DOI: 10.1681/asn.0000000000000373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/29/2024] [Indexed: 05/08/2024] Open
Abstract
Key Points
We evidenced terminal pathway activation (C5b-9 deposits) in most of the glomeruli on kidney biopsy of C3 glomerulopathy.The amount of C5b-9 deposits correlated with disease prognosis in C3 glomerulopathy.Increased terminal pathway activation was found predominantly in a subgroup exhibiting an immuno-fibroblastic signature.
Background
C3 glomerulopathy is a rare disease resulting from an overactivation of the complement alternative pathway. Although there is also evidence of terminal pathway activation, its occurrence and consequences on the disease have been poorly studied.
Methods
We retrospectively studied a cohort of 42 patients diagnosed with C3 glomerulopathy. We performed centralized extensive characterization of histological parameters. Kidney C5b-9 staining was performed as a marker of terminal pathway activation; intrarenal immune response was characterized through transcriptomic analysis.
Results
Eighty-eight percent of biopsies showed C5b-9 deposits in glomeruli. Biopsies were grouped according to the amount of C5b-9 deposits (no or low n=15/42, 36%; intermediate n=15/42, 36%; and high n=12/42, 28%). Patients with high C5b-9 deposits significantly differed from the two other groups of patients and were characterized by a significant higher histological chronicity score (P = 0.005) and lower outcome-free survival (P = 0.001). In multivariable analysis, higher glomerular C5b-9 remained associated with poor kidney prognosis after adjustment. One third of the 847 studied immune genes were upregulated in C3 glomerulopathy biopsies compared with controls. Unsupervised clustering on differentially expressed genes identified a group of kidney biopsies enriched in high glomerular C5b-9 with high immune and fibroblastic signature and showed high chronicity scores on histological examination.
Conclusions
In a cohort of patients with C3 glomerulopathy, intrarenal terminal pathway activation was associated with specific histological phenotype and disease prognosis.
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Affiliation(s)
- Marie-Sophie Meuleman
- Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Paris, France
| | - Florent Petitprez
- Centre for Reproductive Health, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, United Kingdom
| | - Matthew C Pickering
- Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College, London, United Kingdom
| | - Moglie Le Quintrec
- Department of Nephrology, Montpellier University Hospital, Montpellier, France
| | - Mikel Rezola Artero
- Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Paris, France
| | - Anna Duval
- Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Paris, France
- Department of Nephrology, Strasbourg University Hospital, Strasbourg, France
| | - Marion Rabant
- Department of Anathomopathology, Necker Hospital, APHP, Paris, France
- Département Croissance et Signalisation, INSERM U1151, CNRS UMR 8253, Institut Necker-Enfants Malades, Paris, France
| | - Alyssa Gilmore
- Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College, London, United Kingdom
| | - Olivia Boyer
- Pediatric Nephrology, Necker-Enfants Malades University Hospital, MARHEA reference center, APHP, Institut Imagine, Université Paris Cité, Paris, France
| | - Julien Hogan
- Department of pediatric Nephrology, Robert Debré Hospital, APHP, Paris, France
| | - Aude Servais
- Department of Nephrology, Necker-Enfants Malades Hospital, APHP, Paris, France
| | - François Provot
- Department of Nephrology, Lille University Hospital, Lille, France
| | - Vivianne Gnemmi
- Department of Pathology, Lille University Hospital, Lille, France
| | - Maeva Eloudzeri
- Département Croissance et Signalisation, INSERM U1151, CNRS UMR 8253, Institut Necker-Enfants Malades, Paris, France
| | - Anne Grunenwald
- Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Paris, France
- Department of Nephrology, Poissy Intercommunal Hospital, Poissy, France
| | - David Buob
- Department of Pathology, Tenon Hospital, APHP, Paris, France
| | | | - Anissa Moktefi
- Department of Pathology, Henri Mondor Hospital, APHP, Créteil, France
| | - Vincent Audard
- Assistance Publique des Hôpitaux de Paris (AP-HP), Nephrology and Renal Transplantation Department, Henri Mondor Hospital University, Centre de Référence Maladie Rare Syndrome Néphrotique Idiopathique, Fédération Hospitalo-Universitaire Innovative therapy for immune disorders, Créteil, France
- Institut National de la Santé et de la Recherche Médicale (INSERM) U955, Institut Mondor de Recherche Biomédicale (IMRB), Univ Paris Est Créteil, Créteil, France
| | | | - Frank Bridoux
- Department of Nephrology, Poitiers University Hospital, Poitiers, France
| | - Eric Thervet
- Department of Nephrology, European Hospital Georges Pompidou, APHP, Paris, France
- Paris Cité University, Paris, France
| | - Alexandre Karras
- Department of Nephrology, European Hospital Georges Pompidou, APHP, Paris, France
- Paris Cité University, Paris, France
| | - Lubka T Roumenina
- Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Paris, France
| | - Véronique Frémeaux Bacchi
- Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Paris, France
- Department of Immunology, European Hospital Georges Pompidou, APHP, Paris, France
| | - Jean-Paul Duong Van Huyen
- Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Paris, France
- Department of Anathomopathology, Necker Hospital, APHP, Paris, France
- Paris Cité University, Paris, France
| | - Sophie Chauvet
- Inflammation, Complement and Cancer Team, Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Paris, France
- Department of Nephrology, European Hospital Georges Pompidou, APHP, Paris, France
- Paris Cité University, Paris, France
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8
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Madden B, Singh RD, Haas M, Palma LMP, Sharma A, Vargas MJ, Gross L, Negron V, Nate T, Charlesworth MC, Theis JD, Nasr SH, Nath KA, Fervenza FC, Sethi S. Apolipoprotein E is enriched in dense deposits and is a marker for dense deposit disease in C3 glomerulopathy. Kidney Int 2024; 105:1077-1087. [PMID: 38447879 DOI: 10.1016/j.kint.2024.02.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 01/31/2024] [Accepted: 02/02/2024] [Indexed: 03/08/2024]
Abstract
C3 glomerulopathy (C3G) is a rare disease resulting from dysregulation of the alternative pathway of complement. C3G includes C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), both of which are characterized by bright glomerular C3 staining on immunofluorescence studies. However, on electron microscopy (EM), DDD is characterized by dense osmiophilic mesangial and intramembranous deposits along the glomerular basement membranes (GBM), while the deposits of C3GN are not dense. Why the deposits appear dense in DDD and not in C3GN is not known. We performed laser microdissection (LCM) of glomeruli followed by mass spectrometry (MS) in 12 cases each of DDD, C3GN, and pretransplant kidney control biopsies. LCM/MS showed marked accumulation of complement proteins C3, C5, C6, C7, C8, C9 and complement regulating proteins CFHR5, CFHR1, and CFH in C3GN and DDD compared to controls. C3, CFH and CFHR proteins were comparable in C3GN and DDD. Yet, there were significant differences. First, there was a six-to-nine-fold increase of C5-9 in DDD compared to C3GN. Secondly, an unexpected finding was a nine-fold increase in apolipoprotein E (ApoE) in DDD compared to C3GN. Most importantly, immunohistochemical and confocal staining for ApoE mirrored the dense deposit staining in the GBM in DDD but not in C3GN or control cases. Validation studies using 31 C3G cases confirmed the diagnosis of C3GN and DDD in 80.6 % based on ApoE staining. Overall, there is a higher burden of terminal complement pathway proteins in DDD compared to C3GN. Thus, our study shows that dense deposits in DDD are enriched with ApoE compared to C3GN and control cases. Hence, ApoE staining may be used as an adjunct to EM for the diagnosis of DDD and might be valuable when EM is not available.
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Affiliation(s)
- Benjamin Madden
- Mayo Clinic Proteomics Core, Mayo Clinic, Rochester, Minnesota, USA
| | - Raman Deep Singh
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Mark Haas
- Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Lilian M P Palma
- Pediatric Nephrology, State University of Campinas (UNICAMP), Campinas, Brazil
| | - Alok Sharma
- Department of Renal Pathology & Electron Microscopy, Dr Lal Path Labs, New Delhi, India
| | - Maria J Vargas
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - LouAnn Gross
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vivian Negron
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Torell Nate
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Jason D Theis
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Samih H Nasr
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Karl A Nath
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Fernando C Fervenza
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
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9
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Sethi S, Theis JD, Palma LM, Madden B. From Patterns to Proteins: Mass Spectrometry Comes of Age in Glomerular Disease. J Am Soc Nephrol 2024; 35:117-128. [PMID: 37749770 PMCID: PMC10786612 DOI: 10.1681/asn.0000000000000221] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 08/17/2023] [Indexed: 09/27/2023] Open
Abstract
Laser capture microdissection and mass spectrometry (LCM/MS) is a technique that involves dissection of glomeruli from paraffin-embedded biopsy tissue, followed by digestion of the dissected glomerular proteins by trypsin, and subsequently mass spectrometry to identify and semiquantitate the glomerular proteins. LCM/MS has played a crucial role in the identification of novel types of amyloidosis, biomarker discovery in fibrillary GN, and more recently discovery of novel target antigens in membranous nephropathy (MN). In addition, LCM/MS has also confirmed the role for complement proteins in glomerular diseases, including C3 glomerulopathy. LCM/MS is now widely used as a clinical test and considered the gold standard for diagnosis and typing amyloidosis. For the remaining glomerular diseases, LCM/MS has remained a research tool. In this review, we discuss the usefulness of LCM/MS in other glomerular diseases, particularly MN, deposition diseases, and diseases of complement pathways, and advocate more routine use of LCM/MS at the present time in at least certain diseases, such as MN, for target antigen detection. We also discuss the limitations of LCM/MS, particularly the difficulties faced from moving from a research-based technique to a clinical test. Nonetheless, the role of LCM/MS in glomerular diseases is expanding. Currently, LCM/MS may be used to identify the etiology in certain glomerular diseases, but in the future, LCM/MS can play a valuable role in determining pathways of complement activation, inflammation, and fibrosis.
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Affiliation(s)
- Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Jason D. Theis
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Lilian M.P. Palma
- Pediatric Nephrology, State University of Campinas (UNICAMP), Campinas, Brazil
| | - Benjamin Madden
- Mayo Clinic Proteomics Core, Mayo Clinic, Rochester, Minnesota
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10
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Mannes M, Pechtl V, Hafner S, Dopler A, Eriksson O, Manivel VA, Wohlgemuth L, Messerer DAC, Schrezenmeier H, Ekdahl KN, Nilsson B, Jacobsen EM, Hoenig M, Huber-Lang M, Braun CK, Schmidt CQ. Complement and platelets: prothrombotic cell activation requires membrane attack complex-induced release of danger signals. Blood Adv 2023; 7:6367-6380. [PMID: 37428869 PMCID: PMC10625899 DOI: 10.1182/bloodadvances.2023010817] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/20/2023] [Accepted: 07/05/2023] [Indexed: 07/12/2023] Open
Abstract
Complement activation in the diseases paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) results in cytolysis and fatal thrombotic events, which are largely refractory to anticoagulation and/or antiplatelet therapy. Anticomplement therapy, however, efficiently prevents thrombotic events in PNH and aHUS, but the underlying mechanisms remain unresolved. We show that complement-mediated hemolysis in whole blood induces platelet activation similarly to activation by adenosine 5'-diphosphate (ADP). Blockage of C3 or C5 abolished platelet activation. We found that human platelets failed to respond functionally to the anaphylatoxins C3a and C5a. Instead, complement activation did lead to prothrombotic cell activation in the whole blood when membrane attack complex (MAC)-mediated cytolysis occurred. Consequently, we demonstrate that ADP receptor antagonists efficiently inhibited platelet activation, although full complement activation, which causes hemolysis, occurred. By using an established model of mismatched erythrocyte transfusions in rats, we crossvalidated these findings in vivo using the complement inhibitor OmCI and cobra venom factor. Consumptive complement activation in this animal model only led to a thrombotic phenotype when MAC-mediated cytolysis occurred. In conclusion, complement activation only induces substantial prothrombotic cell activation if terminal pathway activation culminates in MAC-mediated release of intracellular ADP. These results explain why anticomplement therapy efficiently prevents thromboembolisms without interfering negatively with hemostasis.
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Affiliation(s)
- Marco Mannes
- Institute of Clinical and Experimental Trauma Immunology, University Hospital of Ulm, Ulm, Germany
| | - Veronika Pechtl
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Ulm, Germany
| | - Susanne Hafner
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Ulm, Germany
| | - Arthur Dopler
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Ulm, Germany
| | - Oskar Eriksson
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Vivek Anand Manivel
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Lisa Wohlgemuth
- Institute of Clinical and Experimental Trauma Immunology, University Hospital of Ulm, Ulm, Germany
| | | | - Hubert Schrezenmeier
- Institute of Transfusion Medicine, University of Ulm and Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, University Hospital of Ulm and German Red Cross Blood Service Baden-Württemberg–Hessen, Ulm, Germany
| | - Kristina N. Ekdahl
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Bo Nilsson
- Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
| | - Eva-Maria Jacobsen
- Department of Pediatrics and Adolescent Medicine, University Hospital of Ulm, Ulm, Germany
| | - Manfred Hoenig
- Department of Pediatrics and Adolescent Medicine, University Hospital of Ulm, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, University Hospital of Ulm, Ulm, Germany
| | - Christian K. Braun
- Department of Pediatrics and Adolescent Medicine, University Hospital of Ulm, Ulm, Germany
| | - Christoph Q. Schmidt
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University of Ulm Medical Center, Ulm, Germany
- Institute of Pharmacy, Biochemical Pharmacy Group, Martin Luther University Halle-Wittenberg, Halle, Germany
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11
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Kareem S, Jacob A, Mathew J, Quigg RJ, Alexander JJ. Complement: Functions, location and implications. Immunology 2023; 170:180-192. [PMID: 37222083 PMCID: PMC10524990 DOI: 10.1111/imm.13663] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 05/09/2023] [Indexed: 05/25/2023] Open
Abstract
The complement system, an arm of the innate immune system plays a critical role in both health and disease. The complement system is highly complex with dual possibilities, helping or hurting the host, depending on the location and local microenvironment. The traditionally known functions of complement include surveillance, pathogen recognition, immune complex trafficking, processing and pathogen elimination. The noncanonical functions of the complement system include their roles in development, differentiation, local homeostasis and other cellular functions. Complement proteins are present in both, the plasma and on the membranes. Complement activation occurs both extra- and intracellularly, which leads to considerable pleiotropy in their activity. In order to design more desirable and effective therapies, it is important to understand the different functions of complement, and its location-based and tissue-specific responses. This manuscript will provide a brief overview into the complex nature of the complement cascade, outlining some of their complement-independent functions, their effects at different locale, and their implication in disease settings.
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Affiliation(s)
- Samer Kareem
- Department of Medicine, University at Buffalo, Buffalo, New York, United States
| | - Alexander Jacob
- Department of Medicine, University at Buffalo, Buffalo, New York, United States
| | - John Mathew
- Department of Rheumatology, Christian Medical College, Vellore, India
| | - Richard J Quigg
- Department of Medicine, University at Buffalo, Buffalo, New York, United States
| | - Jessy J Alexander
- Department of Medicine, University at Buffalo, Buffalo, New York, United States
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12
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Lim JH, Shin SW, Kim MS, Han MH, Kim YJ, Jung HY, Choi JY, Cho JH, Park SH, Kim YL, Hwang D, Yun WS, Kim HK, Huh S, Yoo ES, Won DI, Kim CD. Recurrent C3 Glomerulonephritis along with BK-Virus-Associated Nephropathy after Kidney Transplantation: A Case Report. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1308. [PMID: 37512118 PMCID: PMC10383463 DOI: 10.3390/medicina59071308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 07/12/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023]
Abstract
C3 glomerulonephritis (C3GN) is a rare cause of end-stage kidney disease and frequently recurrent in allografts following kidney transplantation (KT). Herein, we describe the case of a kidney transplant recipient who developed recurrent C3GN along with BK-virus-associated nephropathy (BKVAN) following KT. A 33-year-old man diagnosed with membranoproliferative glomerulonephritis 17 years ago underwent preemptive KT with a donor kidney from his aunt. Proteinuria gradually increased after 3 months following KT, and graft biopsy was performed 30 months after KT. Histopathological examination revealed recurrent C3GN. The dosages of triple immunosuppressive maintenance therapy agents were increased. Subsequently, serum C3 levels recovered to normal levels. However, at 33 months following KT, the BK viral load increased and graft function gradually deteriorated; a second graft biopsy was performed at 46 months following KT, which revealed BKVAN and decreased C3GN activity. The dosages of immunosuppressive agents were decreased; subsequently, BKVAN improved and graft function was maintained with normal serum C3 levels at 49 months following KT. This case indicates that C3GN is highly prone to recurrence following KT and that immunosuppressive therapy for C3GN increases the risk of BKVAN.
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Affiliation(s)
- Jeong-Hoon Lim
- Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Seong-Won Shin
- Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Mee-Seon Kim
- Department of Pathology, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Man-Hoon Han
- Department of Pathology, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Yong-Jin Kim
- Department of Pathology, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Hee-Yeon Jung
- Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Ji-Young Choi
- Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Jang-Hee Cho
- Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Sun-Hee Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Yong-Lim Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Deokbi Hwang
- Department of Surgery, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Woo-Sung Yun
- Department of Surgery, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Hyung-Kee Kim
- Department of Surgery, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Seung Huh
- Department of Surgery, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Eun Sang Yoo
- Department of Urology, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Dong Il Won
- Department of Clinical Pathology, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Chan-Duck Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University Hospital, Kyungpook National University, Daegu 41944, Republic of Korea
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13
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Tomaszewski K, Herlitz L. Complement detection in kidney biopsies - utility and challenges. Curr Opin Nephrol Hypertens 2023; 32:241-248. [PMID: 36811623 DOI: 10.1097/mnh.0000000000000872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Abstract
PURPOSE OF REVIEW This review discusses the important role of staining for components of the complement cascade in both native and transplant kidney biopsies. The use of complement staining as a marker of prognosis, disease activity, and as a potential future tool in identifying patients who may benefit from complement-targeted therapies is discussed. RECENT FINDINGS While staining for C3, C1q and C4d can yield valuable information about complement activation in kidney biopsies, to adequately assess complement activation and potential therapeutic targets, expanded staining panels looking at multiple split products and complement regulatory proteins are needed. Recent progress has been made in identifying markers of disease severity in C3 glomerulonephritis and IgA nephropathy, such as Factor H-related Protein-5, which may serve as future tissue biomarkers. In the transplant setting, the limitation of relying on C4d staining to identify antibody mediated rejection is giving way to molecular diagnostics, including The Banff Human Organ Transplant (B-HOT) panel, which includes numerous complement complement-related transcripts, with the classical, lectin, alternative, and common pathways. SUMMARY Staining for complement components in kidney biopsies to understand how complement is activated in individual cases may help to identify patients who may benefit from complement-targeted therapies.
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14
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Sethi S, Palma LMP, Theis JD, Fervenza FC. Proteomic Analysis of Complement Proteins in Glomerular Diseases. Kidney Int Rep 2023; 8:827-836. [PMID: 37069992 PMCID: PMC10105064 DOI: 10.1016/j.ekir.2023.01.030] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 01/18/2023] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
Introduction Complement plays an important role in the pathogenesis of glomerulonephritis (GN). Even though the underlying etiology of GN might be different, complement activation with subsequent glomerular deposition of complement proteins result in glomerular injury and progression of the lesions. Routine immunofluorescence microscopy (IF) includes staining for only complement factors C3c and C1q. Therefore, with regard to evaluation of the complement pathways, routine kidney biopsy provides only limited information. Methods In this study, using laser microdissection of glomeruli followed by mass spectrometry, complement proteins and pathways involved in GN were analyzed. Results We found that C3 followed by C9 are the most abundant complement proteins in GN, indicating activation of classical or lectin or alternative, and terminal pathways, either exclusively or in a combination of pathways. Furthermore, depending on the type of GN, C4A and/or C4B were also present. Therefore, membranous nephropathy (MN), fibrillary GN, and infection-related GN showed C4A dominant pathways, whereas lupus nephritis (LN), proliferative GN with monoclonal Ig deposits, monoclonal Ig deposition disease (MIDD), and immunotactoid glomerulopathy showed C4B dominant pathways. Significant deposition of complement regulatory proteins, factor H-related protein-1 (FHR-1) and factor H-related protein-5 (FHR-5), were also detected in most GN. Conclusions This study shows accumulation of specific complement proteins in GN. The complement pathways, complement proteins, and the amount of complement protein deposition are variable in different types of GN. Selective targeting of complement pathways may be a novel option in the treatment of GN.
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Affiliation(s)
- Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Jason D. Theis
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
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15
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Noris M, Daina E, Remuzzi G. Membranoproliferative glomerulonephritis: no longer the same disease and may need very different treatment. Nephrol Dial Transplant 2023; 38:283-290. [PMID: 34596686 DOI: 10.1093/ndt/gfab281] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Indexed: 12/17/2022] Open
Abstract
Membranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular injury that may be primary or secondary to infections, autoimmune diseases and haematological disorders. Primary C3G and IC-MPGN are rare and the prognosis is unfavourable. Based on immunofluorescence findings, MPGN has been classified into complement-mediated C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, this classification leaves a number of issues unresolved. The finding of genetic and acquired complement abnormalities in both C3G and IC-MPGN indicates that they represent a heterogeneous spectrum rather than distinct diseases. An unsupervised hierarchical clustering in a cohort of patients with primary C3G and IC-MPGN identified four distinct pathogenetic patterns, characterized by specific histologic and clinical features, and genetic and acquired complement abnormalities. These results provide the groundwork for a more accurate diagnosis and the development of targeted therapies. The drugs that are currently used, such as corticosteroids and immunosuppressants, are frequently ineffective in primary C3G and IC-MPGN. Eculizumab, an anti-C5 monoclonal antibody, has been used occasionally in single cases or small series. However, only a few patients have achieved remission. This heterogeneous response could be related to the extent of terminal complement activation, which may vary substantially from patient to patient. Several drugs that target the complement system at different levels are under investigation for C3G and IC-MPGN. However, clinical trials to test new therapeutics will be challenging and heavily influenced by the heterogeneity of these diseases. This creates the need to characterize each patient to match the specific complement abnormality with the type of intervention.
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Affiliation(s)
- Marina Noris
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Erica Daina
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
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16
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Abstract
Uncontrolled alternative pathway activation is the primary driver of several diseases, and it contributes to the pathogenesis of many others. Consequently, diagnostic tests to monitor this arm of the complement system are increasingly important. Defects in alternative pathway regulation are strong risk factors for disease, and drugs that specifically block the alternative pathway are entering clinical use. A range of diagnostic tests have been developed to evaluate and monitor the alternative pathway, including assays to measure its function, expression of alternative pathway constituents, and activation fragments. Genetic studies have also revealed many disease-associated variants in alternative pathway genes that predict the risk of disease and prognosis. Newer imaging modalities offer the promise of non-invasively detecting and localizing pathologic complement activation. Together, these various tests help in the diagnosis of disease, provide important prognostic information, and can help guide therapy with complement inhibitory drugs.
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Affiliation(s)
- Joshua M. Thurman
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
| | - Veronique Fremeaux-Bacchi
- Assistance Publique-Hôpitaux de Paris, European Hospital Georges Pompidou, Department of Immunology Biology and INSERM UMRS1138, Centre de Recherche des Cordeliers, Team "Inflammation, Complement and Cancer", Paris, France
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17
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Thurman JM, Harrison RA. The susceptibility of the kidney to alternative pathway activation-A hypothesis. Immunol Rev 2023; 313:327-338. [PMID: 36369971 DOI: 10.1111/imr.13168] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The glomerulus is often the prime target of dysregulated alternative pathway (AP) activation. In particular, AP activation is the key driver of two severe kidney diseases: atypical hemolytic uremic syndrome and C3 glomerulopathy. Both conditions are associated with a variety of predisposing molecular defects in AP regulation, such as genetic variants in complement regulators, autoantibodies targeting AP proteins, or autoantibodies that stabilize the AP convertases (C3- and C5-activating enzymes). It is noteworthy that these are systemic AP defects, yet in both diseases pathologic complement activation primarily affects the kidneys. In particular, AP activation is often limited to the glomerular capillaries. This tropism of AP-mediated inflammation for the glomerulus points to a unique interaction between AP proteins in plasma and this particular anatomic structure. In this review, we discuss the pre-clinical and clinical data linking the molecular causes of aberrant control of the AP with activation in the glomerulus, and the possible causes of this tropism. Based on these data, we propose a model for why the kidney is so uniquely and frequently targeted in patients with AP defects. Finally, we discuss possible strategies for preventing pathologic AP activation in the kidney.
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Affiliation(s)
- Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado, USA
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18
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Schmidt CQ, Smith RJH. Protein therapeutics and their lessons: Expect the unexpected when inhibiting the multi-protein cascade of the complement system. Immunol Rev 2023; 313:376-401. [PMID: 36398537 PMCID: PMC9852015 DOI: 10.1111/imr.13164] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Over a century after the discovery of the complement system, the first complement therapeutic was approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). It was a long-acting monoclonal antibody (aka 5G1-1, 5G1.1, h5G1.1, and now known as eculizumab) that targets C5, specifically preventing the generation of C5a, a potent anaphylatoxin, and C5b, the first step in the eventual formation of membrane attack complex. The enormous clinical and financial success of eculizumab across four diseases (PNH, atypical hemolytic uremic syndrome (aHUS), myasthenia gravis (MG), and anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD)) has fueled a surge in complement therapeutics, especially targeting diseases with an underlying complement pathophysiology for which anti-C5 therapy is ineffective. Intensive research has also uncovered challenges that arise from C5 blockade. For example, PNH patients can still face extravascular hemolysis or pharmacodynamic breakthrough of complement suppression during complement-amplifying conditions. These "side" effects of a stoichiometric inhibitor like eculizumab were unexpected and are incompatible with some of our accepted knowledge of the complement cascade. And they are not unique to C5 inhibition. Indeed, "exceptions" to the rules of complement biology abound and have led to unprecedented and surprising insights. In this review, we will describe initial, present and future aspects of protein inhibitors of the complement cascade, highlighting unexpected findings that are redefining some of the mechanistic foundations upon which the complement cascade is organized.
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Affiliation(s)
- Christoph Q. Schmidt
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
| | - Richard J. H. Smith
- Departments of Internal Medicine and Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
- Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
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19
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Gross hematuria, edema, and hypocomplementemia in a 9-year-old boy: Answers. Pediatr Nephrol 2022; 37:2349-2353. [PMID: 35352193 DOI: 10.1007/s00467-022-05539-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 03/03/2022] [Indexed: 10/18/2022]
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20
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Heiderscheit AK, Hauer JJ, Smith RJH. C3 glomerulopathy: Understanding an ultra-rare complement-mediated renal disease. AMERICAN JOURNAL OF MEDICAL GENETICS. PART C, SEMINARS IN MEDICAL GENETICS 2022; 190:344-357. [PMID: 35734939 PMCID: PMC9613507 DOI: 10.1002/ajmg.c.31986] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 04/27/2022] [Accepted: 06/10/2022] [Indexed: 01/29/2023]
Abstract
C3 glomerulopathy (C3G) describes a pathologic pattern of injury diagnosed by renal biopsy. It is characterized by the dominant deposition of the third component of complement (C3) in the renal glomerulus as resolved by immunofluorescence microscopy. The underlying pathophysiology is driven by dysregulation of the alternative pathway of complement in the fluid-phase and in the glomerular microenvironment. Characterization of clinical features and a targeted evaluation for indices and drivers of complement dysregulation are necessary for optimal patient care. Autoantibodies to the C3 and C5 convertases of complement are the most commonly detected drivers of complement dysregulation, although genetic mutations in complement genes can also be found. Approximately half of patients progress to end-stage renal disease within 10 years of diagnosis, and, while transplantation is a viable option, there is high risk for disease recurrence and allograft failure. This poor outcome reflects the lack of disease-specific therapy for C3G, relegating patients to symptomatic treatment to minimize proteinuria and suppress renal inflammation. Fortunately, the future is bright as several anti-complement drugs are currently in clinical trials.
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Affiliation(s)
- Amanda K. Heiderscheit
- Molecular Otolaryngology and Renal Research Laboratories, Carver College of MedicineUniversity of IowaIowa CityIowaUSA,Graduate PhD Program in Immunology, Carver College of MedicineUniversity of IowaIowa CityIowaUSA
| | - Jill J. Hauer
- Molecular Otolaryngology and Renal Research Laboratories, Carver College of MedicineUniversity of IowaIowa CityIowaUSA
| | - Richard J. H. Smith
- Molecular Otolaryngology and Renal Research Laboratories, Carver College of MedicineUniversity of IowaIowa CityIowaUSA,Graduate PhD Program in Immunology, Carver College of MedicineUniversity of IowaIowa CityIowaUSA
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21
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Yoshizawa N, Yamada M, Fujino M, Oda T. Nephritis-Associated Plasmin Receptor (NAPlr): An Essential Inducer of C3-Dominant Glomerular Injury and a Potential Key Diagnostic Biomarker of Infection-Related Glomerulonephritis (IRGN). Int J Mol Sci 2022; 23:ijms23179974. [PMID: 36077377 PMCID: PMC9456382 DOI: 10.3390/ijms23179974] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/11/2022] [Accepted: 08/16/2022] [Indexed: 11/25/2022] Open
Abstract
Nephritis-associated plasmin receptor (NAPlr) was originally isolated from the cytoplasmic fraction of group A Streptococci, and was found to be the same molecule as streptococcal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and plasmin receptor (Plr) on the basis of nucleotide and amino acid sequence homology. Its main functions include GAPDH activity, plasmin-binding capacity, and direct activation of the complement alternative pathway (A-P). Plasmin trapped by deposited NAPlr triggers the degradation of extracellular matrix proteins, such as glomerular basement membranes and mesangial matrix, and the accumulation of macrophages and neutrophils, leading to the induction of plasmin-related endocapillary glomerular inflammation. Deposited NAPlr at glomerular endocapillary site directly activates the complement A-P, and the endocapillary release of complement-related anaphylatoxins, C3a and C5a, amplify the in situ endocapillary glomerular inflammation. Subsequently, circulating and in situ-formed immune complexes participate in the glomerular injury resulting in NAPlr-mediated glomerulonephritis. The disease framework of infection-related glomerulonephritis (IRGN) has been further expanded. GAPDH of various bacteria other than Streptococci have been found to react with anti-NAPlr antibodies and to possess plasmin-binding activities, allowing glomerular NAPlr and plasmin activity to be utilized as key biomarkers of IRGN.
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Affiliation(s)
| | - Muneharu Yamada
- Department of Nephrology and Blood Purification, Kidney Disease Center, Tokyo Medical University Hachioji Medical Center, Tokyo 193-0998, Japan
| | - Masayuki Fujino
- National Institute of Infectious Disease, Tokyo 162-8640, Japan
| | - Takashi Oda
- Department of Nephrology and Blood Purification, Kidney Disease Center, Tokyo Medical University Hachioji Medical Center, Tokyo 193-0998, Japan
- Correspondence: ; Tel.: +81-42-665-5611; Fax: +81-42-665-1796
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22
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Zhang Y, Goodfellow RX, Ghiringhelli Borsa N, Dunlop HC, Presti SA, Meyer NC, Shao D, Roberts SM, Jones MB, Pitcher GR, Taylor AO, Nester CM, Smith RJH. Complement Factor I Variants in Complement-Mediated Renal Diseases. Front Immunol 2022; 13:866330. [PMID: 35619721 PMCID: PMC9127439 DOI: 10.3389/fimmu.2022.866330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 03/08/2022] [Indexed: 11/26/2022] Open
Abstract
C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) are two rare diseases caused by dysregulated activity of the alternative pathway of complement secondary to the presence of genetic and/or acquired factors. Complement factor I (FI) is a serine protease that downregulates complement activity in the fluid phase and/or on cell surfaces in conjunction with one of its cofactors, factor H (FH), complement receptor 1 (CR1/CD35), C4 binding protein (C4BP) or membrane cofactor protein (MCP/CD46). Because altered FI activity is causally related to the pathogenesis of C3G and aHUS, we sought to test functional activity of select CFI missense variants in these two patient cohorts. We identified 65 patients (16, C3G; 48, aHUS; 1 with both) with at least one rare variant in CFI (defined as a MAF < 0.1%). Eight C3G and eleven aHUS patients also carried rare variants in either another complement gene, ADAMTS13 or THBD. We performed comprehensive complement analyses including biomarker profiling, pathway activity and autoantibody testing, and developed a novel FI functional assay, which we completed on 40 patients. Seventy-eight percent of rare CFI variants (31/40) were associated with FI protein levels below the 25th percentile; in 22 cases, FI levels were below the lower limit of normal (type 1 variants). Of the remaining nine variants, which associated with normal FI levels, two variants reduced FI activity (type 2 variants). No patients carried currently known autoantibodies (including FH autoantibodies and nephritic factors). We noted that while rare variants in CFI predispose to complement-mediated diseases, phenotypes are strongly contingent on the associated genetic background. As a general rule, in isolation, a rare CFI variant most frequently leads to aHUS, with the co-inheritance of a CD46 loss-of-function variant driving the onset of aHUS to the younger age group. In comparison, co-inheritance of a gain-of-function variant in C3 alters the phenotype to C3G. Defects in CFH (variants or fusion genes) are seen with both C3G and aHUS. This variability underscores the complexity and multifactorial nature of these two complement-mediated renal diseases.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Richard J. H. Smith
- Molecular Otolaryngology and Renal Research Laboratories, University of Iowa, Iowa City, IA, United States
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23
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Han Z, Ma K, Tao H, Liu H, Zhang J, Sai X, Li Y, Chi M, Nian Q, Song L, Liu C. A Deep Insight Into Regulatory T Cell Metabolism in Renal Disease: Facts and Perspectives. Front Immunol 2022; 13:826732. [PMID: 35251009 PMCID: PMC8892604 DOI: 10.3389/fimmu.2022.826732] [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: 12/01/2021] [Accepted: 01/24/2022] [Indexed: 11/29/2022] Open
Abstract
Kidney disease encompasses a complex set of diseases that can aggravate or start systemic pathophysiological processes through their complex metabolic mechanisms and effects on body homoeostasis. The prevalence of kidney disease has increased dramatically over the last two decades. CD4+CD25+ regulatory T (Treg) cells that express the transcription factor forkhead box protein 3 (Foxp3) are critical for maintaining immune homeostasis and preventing autoimmune disease and tissue damage caused by excessive or unnecessary immune activation, including autoimmune kidney diseases. Recent studies have highlighted the critical role of metabolic reprogramming in controlling the plasticity, stability, and function of Treg cells. They are also likely to play a vital role in limiting kidney transplant rejection and potentially promoting transplant tolerance. Metabolic pathways, such as mitochondrial function, glycolysis, lipid synthesis, glutaminolysis, and mammalian target of rapamycin (mTOR) activation, are involved in the development of renal diseases by modulating the function and proliferation of Treg cells. Targeting metabolic pathways to alter Treg cells can offer a promising method for renal disease therapy. In this review, we provide a new perspective on the role of Treg cell metabolism in renal diseases by presenting the renal microenvironment、relevant metabolites of Treg cell metabolism, and the role of Treg cell metabolism in various kidney diseases.
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Affiliation(s)
- Zhongyu Han
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China.,Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Kuai Ma
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hongxia Tao
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hongli Liu
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiong Zhang
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Xiyalatu Sai
- Affiliated Hospital of Inner Mongolia University for the Nationalities, Tongliao, China
| | - Yunlong Li
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mingxuan Chi
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Qing Nian
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China.,Department of Blood Transfusion Sicuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Linjiang Song
- Reproductive & Women-Children Hospital, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chi Liu
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Sichuan Renal Disease Clinical Research Center, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
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24
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Schmidt CQ, Schrezenmeier H, Kavanagh D. Complement and the prothrombotic state. Blood 2022; 139:1954-1972. [PMID: 34415298 DOI: 10.1182/blood.2020007206] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 06/08/2021] [Indexed: 11/20/2022] Open
Abstract
In 2007 and 2009, the regulatory approval of the first-in-class complement inhibitor eculizumab revolutionized the clinical management of 2 rare, life-threatening clinical conditions: paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Although being completely distinct diseases affecting blood cells and the glomerulus, PNH and aHUS remarkably share several features in their etiology and clinical presentation. An imbalance between complement activation and regulation at host surfaces underlies both diseases precipitating in severe thrombotic events that are largely resistant to anticoagulant and/or antiplatelet therapies. Inhibition of the common terminal complement pathway by eculizumab prevents the frequently occurring thrombotic events responsible for the high mortality and morbidity observed in patients not treated with anticomplement therapy. Although many in vitro and ex vivo studies elaborate numerous different molecular interactions between complement activation products and hemostasis, this review focuses on the clinical evidence that links these 2 fields in humans. Several noninfectious conditions with known complement involvement are scrutinized for common patterns concerning a prothrombotic statues and the occurrence of certain complement activation levels. Next to PNH and aHUS, germline-encoded CD59 or CD55 deficiency (the latter causing the disease complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy), autoimmune hemolytic anemia, (catastrophic) antiphospholipid syndrome, and C3 glomerulopathy are considered. Parallels and distinct features among these conditions are discussed against the background of thrombosis, complement activation, and potential complement diagnostic and therapeutic avenues.
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Affiliation(s)
- Christoph Q Schmidt
- Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, Ulm, Germany
| | - Hubert Schrezenmeier
- Institute of Transfusion Medicine, University of Ulm, Ulm, Germany
- Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, University Hospital of Ulm and German Red Cross Blood Service Baden-Württemberg-Hessen, Ulm, Germany; and
| | - David Kavanagh
- National Renal Complement Therapeutics Centre, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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25
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Vivarelli M, van de Kar N, Labbadia R, Diomedi-Camassei F, Thurman JM. A clinical approach to children with C3 glomerulopathy. Pediatr Nephrol 2022; 37:521-535. [PMID: 34002292 DOI: 10.1007/s00467-021-05088-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/28/2021] [Accepted: 04/20/2021] [Indexed: 11/28/2022]
Abstract
C3 glomerulopathy is a relatively new clinical entity that represents a challenge both to diagnose and to treat. As new therapeutic agents that act as complement inhibitors become available, many with an oral formulation, a better understanding of this disease and of the underlying complement dysregulation driving it has become increasingly useful to optimize patient care. Moreover, recent advances in research have clarified the role of complement in other glomerular diseases in which its role was less established, namely in immune-complex membranoproliferative glomerulonephritis (IC-MPGN), ANCA-vasculitis, IgA nephropathy, and idiopathic membranous nephropathy. Complement inhibitors are being studied in adult and adolescent clinical trials for these indications. This review summarizes current knowledge and future perspectives on every aspect of the diagnosis and management of C3 glomerulopathy and elucidates current understanding of the role of complement in this condition and in other glomerular diseases in children. An overview of ongoing trials involving therapeutic agents targeting complement in glomerular diseases is also provided.
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Affiliation(s)
- Marina Vivarelli
- Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital IRCCS, Piazza S Onofrio 4, 00165, Rome, Italy.
| | - Nicole van de Kar
- Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Raffaella Labbadia
- Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital IRCCS, Piazza S Onofrio 4, 00165, Rome, Italy
| | | | - Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA
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26
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Complement C3-targeted therapy in C3 glomerulopathy, a prototype of complement-mediated kidney diseases. Semin Immunol 2022; 60:101634. [PMID: 35817659 DOI: 10.1016/j.smim.2022.101634] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 06/28/2022] [Accepted: 07/01/2022] [Indexed: 01/15/2023]
Abstract
C3 glomerulopathy (C3G) is a rare and complex kidney disease that primarily affects young adults. Renal outcomes remain poor in the absence of specific treatment. C3G is driven by uncontrolled overactivation of the alternative complement pathway, which is mainly of acquired origin. Functional characterization of complement abnormalities (i.e., autoantibodies targeting complement components and variants in complement genes) identified in patients and experimental models of the disease improved the understanding of the disease, making C3G a prototype of complement-mediated diseases. The contribution of C3 convertase, as well as C5 convertase, in disease occurrence, phenotype, and severity is now well established, offering various potential therapeutic interventions. However, the lack of sufficient efficiency in anti-C5 therapy highlights the extreme complexity of the disease and the need for new therapeutic approaches based on C3 and C3 convertase axis inhibition. Here, we provide an overview of the complement activation mechanism involved in C3G and discuss therapeutic options based on complement inhibitors, with a specific focus on C3 inhibition.
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27
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Blatt NB, Kumar T, Wickman LT, Kanaan HD, Chang A, Zhang PL. Myeloperoxidase immunohistochemical staining can identify glomerular endothelial cell injury in dense deposit disease. Pediatr Nephrol 2021; 36:4003-4007. [PMID: 34522991 DOI: 10.1007/s00467-021-05262-x] [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: 06/05/2021] [Revised: 07/11/2021] [Accepted: 07/29/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND Previous studies have demonstrated residual complement-mediated deposits in repeat kidney biopsies of C3 glomerulopathies (C3G) (dense deposit disease (DDD) and C3 glomerulonephritis) following eculizumab treatment, despite some clinical improvement. With residual complement deposition, it is difficult to determine whether there is a reduced complement-mediated endothelial cell injury. We validated that myeloperoxidase (MPO) immunohistochemical staining identified glomerular endothelial cell injury in crescentic glomerulonephritis and C3G. CASE (DIAGNOSIS/TREATMENT) We report that MPO staining in the glomerular endothelium of the post-treatment kidney biopsy was significantly reduced after 3 years of eculizumab treatment and clinical improvement in a 5-year-old boy with initial DDD and secondary crescent formation. CONCLUSION We find that immunostaining for MPO is a useful method to compare glomerular endothelial injury in C3G following eculizumab treatment. This finding also supports the notion that eculizumab, a C5 blocker, may not mainly block C3 deposits in the glomeruli but significantly blocks final activation of the complement cascade, thus reducing glomerular endothelial cell injury.
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Affiliation(s)
- Neal B Blatt
- Division of Pediatric Nephrology, Beaumont Health, Royal Oak, MI, USA.
| | - Tripti Kumar
- Department of Pathology, Ascension Providence Hospital, Southfield, MI, USA
| | - Larysa T Wickman
- Division of Pediatric Nephrology, Beaumont Health, Royal Oak, MI, USA
| | - Hassan D Kanaan
- Department of Pathology, Beaumont Laboratories, Beaumont Health, Royal Oak, MI, USA
| | - Anthony Chang
- The University of Chicago Medical Center, Chicago, IL, USA
| | - Ping L Zhang
- Department of Pathology, Beaumont Laboratories, Beaumont Health, Royal Oak, MI, USA.
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28
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Freiwald T, Afzali B. Renal diseases and the role of complement: Linking complement to immune effector pathways and therapeutics. Adv Immunol 2021; 152:1-81. [PMID: 34844708 PMCID: PMC8905641 DOI: 10.1016/bs.ai.2021.09.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The complement system is an ancient and phylogenetically conserved key danger sensing system that is critical for host defense against pathogens. Activation of the complement system is a vital component of innate immunity required for the detection and removal of pathogens. It is also a central orchestrator of adaptive immune responses and a constituent of normal tissue homeostasis. Once complement activation occurs, this system deposits indiscriminately on any cell surface in the vicinity and has the potential to cause unwanted and excessive tissue injury. Deposition of complement components is recognized as a hallmark of a variety of kidney diseases, where it is indeed associated with damage to the self. The provenance and the pathophysiological role(s) played by complement in each kidney disease is not fully understood. However, in recent years there has been a renaissance in the study of complement, with greater appreciation of its intracellular roles as a cell-intrinsic system and its interplay with immune effector pathways. This has been paired with a profusion of novel therapeutic agents antagonizing complement components, including approved inhibitors against complement components (C)1, C3, C5 and C5aR1. A number of clinical trials have investigated the use of these more targeted approaches for the management of kidney diseases. In this review we present and summarize the evidence for the roles of complement in kidney diseases and discuss the available clinical evidence for complement inhibition.
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Affiliation(s)
- Tilo Freiwald
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD, United States; Department of Nephrology, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany
| | - Behdad Afzali
- Department of Nephrology, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany.
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29
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Lemaire M, Noone D, Lapeyraque AL, Licht C, Frémeaux-Bacchi V. Inherited Kidney Complement Diseases. Clin J Am Soc Nephrol 2021; 16:942-956. [PMID: 33536243 PMCID: PMC8216622 DOI: 10.2215/cjn.11830720] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
In the past 20 years, we have witnessed tremendous advances in our ability to diagnose and treat genetic diseases of the kidney caused by complement dysregulation. Staggering progress was realized toward a better understanding of the genetic underpinnings and pathophysiology of many forms of atypical hemolytic uremic syndrome (aHUS) and C3-dominant glomerulopathies that are driven by complement system abnormalities. Many of these seminal discoveries paved the way for the design and characterization of several innovative therapies, some of which have already radically improved patients' outcomes. This review offers a broad overview of the exciting developments that have occurred in the recent past, with a particular focus on single-gene (or Mendelian), complement-driven aHUS and C3-dominant glomerulopathies that should be of interest to both nephrologists and kidney researchers. The discussion is restricted to genes with robust associations with both aHUS and C3-dominant glomerulopathies (complement factor H, complement component 3, complement factor H-related proteins) or only aHUS (complement factor B, complement factor I, and membrane cofactor protein). Key questions and challenges are highlighted, along with potential avenues for future directions.
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Affiliation(s)
- Mathieu Lemaire
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada,Cell Biology Program, SickKids Research Institute, Toronto, Ontario, Canada,Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Damien Noone
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada,Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Anne-Laure Lapeyraque
- Division of Nephrology, Sainte-Justine University Hospital Center, Montreal, Quebec, Canada,Department of Pediatrics, Faculty of Medicine, University of Montréal, Québec, Canada
| | - Christoph Licht
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada,Cell Biology Program, SickKids Research Institute, Toronto, Ontario, Canada,Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Véronique Frémeaux-Bacchi
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Laboratory of Immunology, Paris, France
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30
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Lemaire M, Noone D, Lapeyraque AL, Licht C, Frémeaux-Bacchi V. Inherited Kidney Complement Diseases. CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY : CJASN 2021. [PMID: 33536243 DOI: 10.2215/cjn.11830720)] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
In the past 20 years, we have witnessed tremendous advances in our ability to diagnose and treat genetic diseases of the kidney caused by complement dysregulation. Staggering progress was realized toward a better understanding of the genetic underpinnings and pathophysiology of many forms of atypical hemolytic uremic syndrome (aHUS) and C3-dominant glomerulopathies that are driven by complement system abnormalities. Many of these seminal discoveries paved the way for the design and characterization of several innovative therapies, some of which have already radically improved patients' outcomes. This review offers a broad overview of the exciting developments that have occurred in the recent past, with a particular focus on single-gene (or Mendelian), complement-driven aHUS and C3-dominant glomerulopathies that should be of interest to both nephrologists and kidney researchers. The discussion is restricted to genes with robust associations with both aHUS and C3-dominant glomerulopathies (complement factor H, complement component 3, complement factor H-related proteins) or only aHUS (complement factor B, complement factor I, and membrane cofactor protein). Key questions and challenges are highlighted, along with potential avenues for future directions.
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Affiliation(s)
- Mathieu Lemaire
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada .,Cell Biology Program, SickKids Research Institute, Toronto, Ontario, Canada.,Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Damien Noone
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Anne-Laure Lapeyraque
- Division of Nephrology, Sainte-Justine University Hospital Center, Montreal, Quebec, Canada.,Department of Pediatrics, Faculty of Medicine, University of Montréal, Québec, Canada
| | - Christoph Licht
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada.,Cell Biology Program, SickKids Research Institute, Toronto, Ontario, Canada.,Department of Paediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Véronique Frémeaux-Bacchi
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Laboratory of Immunology, Paris, France
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31
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Koopman JJE, van Essen MF, Rennke HG, de Vries APJ, van Kooten C. Deposition of the Membrane Attack Complex in Healthy and Diseased Human Kidneys. Front Immunol 2021; 11:599974. [PMID: 33643288 PMCID: PMC7906018 DOI: 10.3389/fimmu.2020.599974] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 12/21/2020] [Indexed: 12/11/2022] Open
Abstract
The membrane attack complex-also known as C5b-9-is the end-product of the classical, lectin, and alternative complement pathways. It is thought to play an important role in the pathogenesis of various kidney diseases by causing cellular injury and tissue inflammation, resulting in sclerosis and fibrosis. These deleterious effects are, consequently, targeted in the development of novel therapies that inhibit the formation of C5b-9, such as eculizumab. To clarify how C5b-9 contributes to kidney disease and to predict which patients benefit from such therapy, knowledge on deposition of C5b-9 in the kidney is essential. Because immunohistochemical staining of C5b-9 has not been routinely conducted and never been compared across studies, we provide a review of studies on deposition of C5b-9 in healthy and diseased human kidneys. We describe techniques to stain deposits and compare the occurrence of deposits in healthy kidneys and in a wide spectrum of kidney diseases, including hypertensive nephropathy, diabetic nephropathy, membranous nephropathy, IgA nephropathy, lupus nephritis, C3 glomerulopathy, and thrombotic microangiopathies such as the atypical hemolytic uremic syndrome, vasculitis, interstitial nephritis, acute tubular necrosis, kidney tumors, and rejection of kidney transplants. We summarize how these deposits are related with other histological lesions and clinical characteristics. We evaluate the prognostic relevance of these deposits in the light of possible treatment with complement inhibitors.
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Affiliation(s)
- Jacob J E Koopman
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
- Division of Nephrology, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Mieke F van Essen
- Division of Nephrology, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Helmut G Rennke
- Division of Renal Pathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Aiko P J de Vries
- Division of Nephrology, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Cees van Kooten
- Division of Nephrology, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
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32
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Turkmen K, Baloglu I, Ozer H. C3 glomerulopathy and atypical hemolytic uremic syndrome: an updated review of the literature on alternative complement pathway disorders. Int Urol Nephrol 2021; 53:2067-2080. [PMID: 33389509 DOI: 10.1007/s11255-020-02729-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 12/02/2020] [Indexed: 11/30/2022]
Abstract
The complement system plays a significant role within the pathological process of C3 glomerulopathy (C3GP) and atypical hemolytic uremic syndrome (aHUS). In daily practice, clinicians should differentiate the subgroups of C3GP because of they should apply different treatment modalities. In the past, C3GP was considered as a part of membranoproliferative glomerulonephritis (MPGN). MPGN is defined as glomerular capillary thickening secondary to the synthesis of the new glomerular basement membrane and mesangial cellular hyperplasia with mesangial matrix expansion. Atypical hemolytic uremic syndrome is an ultra-rare disease that can be outlined by the triad of Coombs negative microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Recent advances demonstrated that these diseases share common abnormalities of the control of the alternative complement system. Therefore, nowadays, most researchers advocate that there may be overlap in the pathogenesis of C3GP and aHUS. This review will provide recent novel mechanisms and treatment options in these diseases. For the purposes that we mentioned above and to help clinicians, we aimed to describe the etiology, pathophysiology, and treatment of C3GP and aHUS in this comprehensive review.
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Affiliation(s)
- Kultigin Turkmen
- Department of Nephrology, Necmettin Erbakan University Meram School of Medicine, Konya, Turkey.
| | - Ismail Baloglu
- Department of Nephrology, Necmettin Erbakan University Meram School of Medicine, Konya, Turkey
| | - Hakan Ozer
- Department of Nephrology, Necmettin Erbakan University Meram School of Medicine, Konya, Turkey
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Cavanaugh C, Okusa MD. The Evolving Role of Novel Biomarkers in Glomerular Disease: A Review. Am J Kidney Dis 2021; 77:122-131. [DOI: 10.1053/j.ajkd.2020.06.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/06/2020] [Indexed: 02/06/2023]
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34
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Meri S, Haapasalo K. Function and Dysfunction of Complement Factor H During Formation of Lipid-Rich Deposits. Front Immunol 2020; 11:611830. [PMID: 33363547 PMCID: PMC7753009 DOI: 10.3389/fimmu.2020.611830] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 11/09/2020] [Indexed: 01/19/2023] Open
Abstract
Complement-mediated inflammation or dysregulation in lipid metabolism are associated with the pathogenesis of several diseases. These include age-related macular degeneration (AMD), C3 glomerulonephritis (C3GN), dense deposit disease (DDD), atherosclerosis, and Alzheimer's disease (AD). In all these diseases, formation of characteristic lipid-rich deposits is evident. Here, we will discuss molecular mechanisms whereby dysfunction of complement, and especially of its key regulator factor H, could be involved in lipid accumulation and related inflammation. The genetic associations to factor H polymorphisms, the role of factor H in the resolution of inflammation in lipid-rich deposits, modification of macrophage functions, and complement-mediated clearance of apoptotic and damaged cells indicate that the function of factor H is crucial in limiting inflammation in these diseases.
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Affiliation(s)
- Seppo Meri
- Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
- Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Karita Haapasalo
- Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
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35
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Treatment of C3 Glomerulopathy in Adult Kidney Transplant Recipients: A Systematic Review. Med Sci (Basel) 2020; 8:medsci8040044. [PMID: 33096866 PMCID: PMC7712822 DOI: 10.3390/medsci8040044] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/09/2020] [Accepted: 10/19/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND C3 glomerulopathy (C3G), a rare glomerular disease mediated by alternative complement pathway dysregulation, is associated with a high rate of recurrence and graft loss after kidney transplantation (KTx). We aimed to assess the efficacy of different treatments for C3G recurrence after KTx. METHODS Databases (MEDLINE, EMBASE, and Cochrane Database) were searched from inception through 3 May, 2019. Studies were included that reported outcomes of adult KTx recipients with C3G. Effect estimates from individual studies were combined using the random-effects, generic inverse variance method of DerSimonian and Laird., The protocol for this meta-analysis is registered with PROSPERO (no. CRD42019125718). RESULTS Twelve studies (7 cohort studies and 5 case series) consisting of 122 KTx patients with C3G (73 C3 glomerulonephritis (C3GN) and 49 dense deposit disease (DDD)) were included. The pooled estimated rates of allograft loss among KTx patients with C3G were 33% (95% CI: 12-57%) after eculizumab, 42% (95% CI: 2-89%) after therapeutic plasma exchange (TPE), and 81% (95% CI: 50-100%) after rituximab. Subgroup analysis based on type of C3G was performed. Pooled estimated rates of allograft loss in C3GN KTx patients were 22% (95% CI: 5-46%) after eculizumab, 56% (95% CI: 6-100%) after TPE, and 70% (95% CI: 24-100%) after rituximab. Pooled estimated rates of allograft loss in DDD KTx patients were 53% (95% CI: 0-100%) after eculizumab. Data on allograft loss in DDD after TPE (1 case series, 0/2 (0%) allograft loss at 6 months) and rituximab (1 cohort, 3/3 (100%) allograft loss) were limited. Among 66 patients (38 C3GN, 28 DDD) who received no treatment (due to stable allograft function at presentation and/or clinical judgment of physicians), pooled estimated rates of allograft loss were 32% (95% CI: 7-64%) and 53% (95% CI: 28-77%) for C3GN and DDD, respectively. Among treated C3G patients, data on soluble membrane attack complex of complement (sMAC) were limited to patients treated with eculizumab (N = 7). 80% of patients with elevated sMAC before eculizumab responded to treatment. In addition, all patients who responded to eculizumab had normal sMAC levels after post-eculizumab. CONCLUSIONS Our study suggests that the lowest incidence of allograft loss (33%) among KTX patients with C3G are those treated with eculizumab. Among those who received no treatment for C3G due to stable allograft function, there is a high incidence of allograft loss of 32% in C3GN and 53% in DDD. sMAC level may help to select good responders to eculizumab.
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Kárpáti É, Papp A, Schneider AE, Hajnal D, Cserhalmi M, Csincsi ÁI, Uzonyi B, Józsi M. Interaction of the Factor H Family Proteins FHR-1 and FHR-5 With DNA and Dead Cells: Implications for the Regulation of Complement Activation and Opsonization. Front Immunol 2020; 11:1297. [PMID: 32765490 PMCID: PMC7378360 DOI: 10.3389/fimmu.2020.01297] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 05/22/2020] [Indexed: 12/14/2022] Open
Abstract
Complement plays an essential role in the opsonophagocytic clearance of apoptotic/necrotic cells. Dysregulation of this process may lead to inflammatory and autoimmune diseases. Factor H (FH), a major soluble complement inhibitor, binds to dead cells and inhibits excessive complement activation on their surface, preventing lysis, and the release of intracellular material, including DNA. The FH-related (FHR) proteins share common ligands with FH, due to their homology with this complement regulator, but they lack the domains that mediate the complement inhibitory activity of FH. Because their roles in complement regulation is controversial and incompletely understood, we studied the interaction of FHR-1 and FHR-5 with DNA and dead cells and investigated whether they influence the regulatory role of FH and the complement activation on DNA and dead cells. FH, FHR-1, and FHR-5 bound to both plasmid DNA and human genomic DNA, where both FHR proteins inhibited FH-DNA interaction. The FH cofactor activity was inhibited by FHR-1 and FHR-5 due to the reduced binding of FH to DNA in the presence of the FHRs. Both FHRs caused increased complement activation on DNA. FHR-1 and FHR-5 bound to late apoptotic and necrotic cells and recruited monomeric C-reactive protein and pentraxin 3, and vice versa. Interactions of the FHRs with pentraxins resulted in enhanced activation of both the classical and the alternative complement pathways on dead cells when exposed to human serum. Altogether, our results demonstrate that FHR-1 and FHR-5 are competitive inhibitors of FH on DNA; moreover, FHR-pentraxin interactions promote opsonization of dead cells.
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Affiliation(s)
- Éva Kárpáti
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Alexandra Papp
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Andrea E Schneider
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Dávid Hajnal
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Marcell Cserhalmi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Ádám I Csincsi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Barbara Uzonyi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,MTA-ELTE Complement Research Group, Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Mihály Józsi
- Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary.,MTA-ELTE Complement Research Group, Department of Immunology, ELTE Eötvös Loránd University, Budapest, Hungary
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37
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Fakhouri F, Le Quintrec M, Frémeaux-Bacchi V. Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties. Kidney Int 2020; 98:1135-1148. [PMID: 32622830 DOI: 10.1016/j.kint.2020.05.053] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 05/06/2020] [Accepted: 05/27/2020] [Indexed: 01/11/2023]
Abstract
In recent years, a substantial body of experimental and clinical work has been devoted to C3 glomerulopathy and Ig-mediated membranoproliferative glomerulonephritis. Despite the rapid accumulation of data, several uncertainties about these 2 rare forms of nephropathies persist. They concern their pathophysiology, classification, clinical course, relevance of biomarkers and of pathology findings, and assessment of the efficacy of the available therapies. The present review discusses the impact of these uncertainties on the clinical management of patients.
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Affiliation(s)
- Fadi Fakhouri
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
| | - Moglie Le Quintrec
- Department of nephrology, Université de Montpellier, CHU de Montpellier, Montpellier, France
| | - Véronique Frémeaux-Bacchi
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie and Paris University, Paris, France
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38
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Proteomic Analysis of Complement Proteins in Membranous Nephropathy. Kidney Int Rep 2020; 5:618-626. [PMID: 32405583 PMCID: PMC7210748 DOI: 10.1016/j.ekir.2020.01.018] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 01/08/2020] [Accepted: 01/21/2020] [Indexed: 12/13/2022] Open
Abstract
Introduction Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasian adults. Phospholipase A2 receptor (PLA2R)– and exostosin 1 (EXT1)/exostosin 2 (EXT2)–associated MN represent the most common primary and secondary forms of MN. The complement profile using a proteomics approach has not been studied in these 2 common forms of MN. Methods We used laser microdissection and mass spectrometry (MS/MS) to dissect glomeruli and identify glomerular complement proteins in PLA2R-associated (n = 7), EXT1/EXT2-associated MN (n = 21), and 11 control cases (time 0 transplant biopsies). Results MS/MS identified high total spectral counts for PLA2R and EXT1/EXT2 in corresponding cases of PLA2R- and EXT1/EXT2-positive MN. Both PLA2R- and EXT1/EXT2-associated MN had high spectral counts of complement proteins C3, C4, C5, C6, C7, C8, and C9. Complement protein C1 was present in low spectral counts in EXT1/EXT2-associated MN. Regulators of complement activation that were detected in MN included higher spectral counts of FH, FHR-1, FHR-5, clusterin, vitronectin and lower spectral counts of FHR-3, FHR-4, and CD59. Low spectral counts of FB and properdin, key components of the alternative pathway, also were detected. IgG4 and IgG1 were the most abundant IgG subclasses in PLA2R- and EXT1/EXT2-associated MN. Lower spectral counts for C3, C4, and C5 were detected in control cases when compared with MN. Conclusion Significant complement activation is present in MN as evidenced by large spectral counts of complement proteins from C3- and C4-based pathways, including regulatory proteins of complement pathways. These data suggest that anticomplement drugs may be effective in treatment for MN.
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Kumar A, Nada R, Ramachandran R, Rawat A, Tiewsoh K, Das R, Rayat CS, Gupta KL, Vasishta RK. Outcome of C3 glomerulopathy patients: largest single-centre experience from South Asia. J Nephrol 2019; 33:539-550. [PMID: 31820418 DOI: 10.1007/s40620-019-00672-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 11/11/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND C3 glomerulopathy (C3G) is related to dysfunction of alternative complement pathway (ACP) because of its hyperactivation. Triggering factors and genetic profile are likely to be different in developing countries as compared to the Western world. Data regarding C3G from South Asian is scanty. STUDY DESIGN In the present study, 115 patients of C3G from 2012 to 2017 were analyzed. Clinical details were reviewed; serological levels of C3, C4, complement factor H or B and autoantibody testing was done by nephelometry/ELISA. Limited genetics workup for CFH and CFHR5 genes was done. RESULTS The prevalence of C3G was 1.52%. There was no difference in demographic and histopathologic profiles of C3G patients. Majority of patients had low functional assay and C3 levels. C3 nephritic factor was present in 47.5% of DDD and 38.6% of C3GN. Autoantibodies to CFH were present more often in the patients of C3GN (29.5%) than DDD (12.5%). Autoantibodies to CFB were equally common in both groups. Past history of infections was present in one-third patients and monoclonal paraproteins were present only in two patients. No pathogenic variants were noted in CFH/CFHR5 gene. On follow-up (3.2 + 1.6 years), complete and partial remission was achieved in one-fourth patients and 26% had resistance disease. About 40% progressed to ESRD and 18 underwent renal transplantation of which nine had a post-transplant recurrence. CONCLUSIONS Indian cohort had some differences in the immunological and genetic profile when compared to the Western literature; most significant was the absence of monoclonal immunoglobulins as a trigger for C3G.
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Affiliation(s)
- Ashwani Kumar
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Ritambhra Nada
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.
| | - Raja Ramachandran
- Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Amit Rawat
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Karalanglin Tiewsoh
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Reena Das
- Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Charan Singh Rayat
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Krishan Lal Gupta
- Department of Nephrology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Rakesh Kumar Vasishta
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
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Fung AWS, Sugumar V, Ren AH, Kulasingam V. Emerging role of clinical mass spectrometry in pathology. J Clin Pathol 2019; 73:61-69. [PMID: 31690564 DOI: 10.1136/jclinpath-2019-206269] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 10/14/2019] [Indexed: 12/20/2022]
Abstract
Mass spectrometry-based assays have been increasingly implemented in various disciplines in clinical diagnostic laboratories for their combined advantages in multiplexing capacity and high analytical specificity and sensitivity. It is now routinely used in areas including reference methods development, therapeutic drug monitoring, toxicology, endocrinology, paediatrics, immunology and microbiology to identify and quantify biomolecules in a variety of biological specimens. As new ionisation methods, instrumentation and techniques are continuously being improved and developed, novel mass spectrometry-based clinical applications will emerge for areas such as proteomics, metabolomics, haematology and anatomical pathology. This review will summarise the general principles of mass spectrometry and specifically highlight current and future clinical applications in anatomical pathology.
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Affiliation(s)
- Angela W S Fung
- Department of Pathology and Laboratory Medicine, St Paul's Hospital, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Vijithan Sugumar
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Annie He Ren
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Vathany Kulasingam
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada .,Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada
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Affiliation(s)
- Vivette D. D’Agati
- Department of Pathology and Cell Biology, Division of Nephrology, Columbia University Medical Center, New York, New York, USA
| | - Andrew S. Bomback
- Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, New York, USA
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Van Avondt K, Nur E, Zeerleder S. Mechanisms of haemolysis-induced kidney injury. Nat Rev Nephrol 2019; 15:671-692. [PMID: 31455889 DOI: 10.1038/s41581-019-0181-0] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/10/2019] [Indexed: 12/16/2022]
Abstract
Intravascular haemolysis is a fundamental feature of chronic hereditary and acquired haemolytic anaemias, including those associated with haemoglobinopathies, complement disorders and infectious diseases such as malaria. Destabilization of red blood cells (RBCs) within the vasculature results in systemic inflammation, vasomotor dysfunction, thrombophilia and proliferative vasculopathy. The haemoprotein scavengers haptoglobin and haemopexin act to limit circulating levels of free haemoglobin, haem and iron - potentially toxic species that are released from injured RBCs. However, these adaptive defence systems can fail owing to ongoing intravascular disintegration of RBCs. Induction of the haem-degrading enzyme haem oxygenase 1 (HO1) - and potentially HO2 - represents a response to, and endogenous defence against, large amounts of cellular haem; however, this system can also become saturated. A frequent adverse consequence of massive and/or chronic haemolysis is kidney injury, which contributes to the morbidity and mortality of chronic haemolytic diseases. Intravascular destruction of RBCs and the resulting accumulation of haemoproteins can induce kidney injury via a number of mechanisms, including oxidative stress and cytotoxicity pathways, through the formation of intratubular casts and through direct as well as indirect proinflammatory effects, the latter via the activation of neutrophils and monocytes. Understanding of the detailed pathophysiology of haemolysis-induced kidney injury offers opportunities for the design and implementation of new therapeutic strategies to counteract the unfavourable and potentially fatal effects of haemolysis on the kidney.
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Affiliation(s)
- Kristof Van Avondt
- Department of Immunopathology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. .,Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University of Munich, Munich, Germany.
| | - Erfan Nur
- Department of Haematology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Sacha Zeerleder
- Department of Immunopathology, Sanquin Research, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. .,Department of Haematology and Central Haematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. .,Department for BioMedical Research, University of Bern, Bern, Switzerland.
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Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy. Pediatr Nephrol 2019; 34:1311-1323. [PMID: 29948306 DOI: 10.1007/s00467-018-3989-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 05/08/2018] [Accepted: 05/25/2018] [Indexed: 02/08/2023]
Abstract
Membranoproliferative glomerulonephritis (MPGN) is a rare chronic kidney disease associated with complement activation. Recent immunofluorescence-based classification distinguishes between immune complex (IC)-mediated MPGN, with glomerular IgG and C3 deposits, and C3 glomerulopathies (C3G), with predominant C3 deposits. Genetic and autoimmune abnormalities causing hyperactivation of the complement alternative pathway have been found as frequently in patients with immune complex-associated MPGN (IC-MPGN) as in those with C3G. In the last decade, there have been great advances in research into the autoimmune causes of IC-MPGN and C3G. The complement-activating autoantibodies called C3-nephritic factors (C3NeFs), which are present in 40-80% of patients, form a heterogeneous group of autoantibodies that stabilise the C3 convertase or the C5 convertase of the alternative pathway or both. A few patients, mainly with IC-MPGN, carry autoantibodies directed against the two components of the alternative pathway C3 convertase, factors B and C3b. Finally, autoantibodies against factor H, the main regulator of the alternative pathway, have been reported in a small proportion of patients with IC-MPGN or C3G. The identification of distinct pathogenetic patterns leading to kidney injury and of targets in the complement cascade may pave the way for tailored therapies for IC-MPGN and C3G, with specific complement inhibitors in the development pipeline.
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Hohenstein B, Amann K, Menne J. Membranoproliferative Glomerulonephritis und C3‑Glomerulopathie. Internist (Berl) 2019; 60:458-467. [DOI: 10.1007/s00108-019-0572-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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Smith RJH, Appel GB, Blom AM, Cook HT, D'Agati VD, Fakhouri F, Fremeaux-Bacchi V, Józsi M, Kavanagh D, Lambris JD, Noris M, Pickering MC, Remuzzi G, de Córdoba SR, Sethi S, Van der Vlag J, Zipfel PF, Nester CM. C3 glomerulopathy - understanding a rare complement-driven renal disease. Nat Rev Nephrol 2019; 15:129-143. [PMID: 30692664 PMCID: PMC6876298 DOI: 10.1038/s41581-018-0107-2] [Citation(s) in RCA: 232] [Impact Index Per Article: 38.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The C3 glomerulopathies are a group of rare kidney diseases characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment, which results in prominent complement C3 deposition in kidney biopsy samples. The two major subgroups of C3 glomerulopathy - dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) - have overlapping clinical and pathological features suggestive of a disease continuum. Dysregulation of the complement alternative pathway is fundamental to the manifestations of C3 glomerulopathy, although terminal pathway dysregulation is also common. Disease is driven by acquired factors in most patients - namely, autoantibodies that target the C3 or C5 convertases. These autoantibodies drive complement dysregulation by increasing the half-life of these vital but normally short-lived enzymes. Genetic variation in complement-related genes is a less frequent cause. No disease-specific treatments are available, although immunosuppressive agents and terminal complement pathway blockers are helpful in some patients. Unfortunately, no treatment is universally effective or curative. In aggregate, the limited data on renal transplantation point to a high risk of disease recurrence (both DDD and C3GN) in allograft recipients. Clinical trials are underway to test the efficacy of several first-generation drugs that target the alternative complement pathway.
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Affiliation(s)
- 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, IA, USA.
| | - Gerald B Appel
- Department of Nephrology, Columbia University, New York, NY, USA
| | - Anna M Blom
- Department of Translational Medicine, Lund University, Malmö, Sweden
| | - H Terence Cook
- Centre for Inflammatory Disease, Imperial College London, London, UK
| | - Vivette D D'Agati
- Department of Pathology, Renal Pathology Laboratory, Columbia University Medical Center, New York, NY, USA
| | - Fadi Fakhouri
- Department of Nephrology and Immunology, Centre Hospitalier et Universitaire de Nantes, Nantes, France
| | - Véronique Fremeaux-Bacchi
- Service de Néphrologie-Transplantation Adulte, Hôpital Necker-Enfants Malades, Université Paris Descartes, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Mihály Józsi
- Complement Research Group, Department of Immunology, ELTE Eötvös Loránd University and the MTA-SE Research Group of Immunology and Haematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary
| | - David Kavanagh
- Newcastle University, Institute of Genetic Medicine, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK
| | - John D Lambris
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Marina Noris
- Istituto di Ricerche Farmacologiche (IRCCS) 'Mario Negri', Clinical Research Centre for Rare Diseases 'Aldo e Cele Daccò', Ranica, Bergamo, Italy
| | | | - Giuseppe Remuzzi
- Istituto di Ricerche Farmacologiche (IRCCS) 'Mario Negri', Clinical Research Centre for Rare Diseases 'Aldo e Cele Daccò', Ranica, Bergamo, Italy
- Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
- Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy
| | - Santiago Rodriguez de Córdoba
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain
| | - Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Johan Van der Vlag
- Department of Nephrology, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Peter F Zipfel
- Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany
- Friedrich Schiller University, Jena, Germany
| | - Carla M Nester
- 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, IA, USA
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Nissilä E, Hakala P, Leskinen K, Roig A, Syed S, Van Kessel KPM, Metso J, De Haas CJC, Saavalainen P, Meri S, Chroni A, Van Strijp JAG, Öörni K, Jauhiainen M, Jokiranta TS, Haapasalo K. Complement Factor H and Apolipoprotein E Participate in Regulation of Inflammation in THP-1 Macrophages. Front Immunol 2018; 9:2701. [PMID: 30519244 PMCID: PMC6260146 DOI: 10.3389/fimmu.2018.02701] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 11/01/2018] [Indexed: 12/28/2022] Open
Abstract
The alternative pathway (AP) of complement is constantly active in plasma and can easily be activated on self surfaces and trigger local inflammation. Host cells are protected from AP attack by Factor H (FH), the main AP regulator in plasma. Although complement is known to play a role in atherosclerosis, the mechanisms of its contribution are not fully understood. Since FH via its domains 5-7 binds apoliporotein E (apoE) and macrophages produce apoE we examined how FH could be involved in the antiatherogenic effects of apoE. We used blood peripheral monocytes and THP-1 monocyte/macrophage cells which were also loaded with acetylated low-density lipoprotein (LDL) to form foam cells. Binding of FH and apoE on these cells was analyzed by flow cytometry. High-density lipoprotein (HDL)-mediated cholesterol efflux of activated THP-1 cells was measured and transcriptomes of THP-1 cells using mRNA sequencing were determined. We found that binding of FH to human blood monocytes and cholesterol-loaded THP-1 macrophages increased apoE binding to these cells. Preincubation of fluorescent cholesterol labeled THP-1 macrophages in the presence of FH increased cholesterol efflux and cholesterol-loaded macrophages displayed reduced transcription of proinflammatory/proatherogenic factors and increased transcription of anti-inflammatory/anti-atherogenic factors. Further incubation of THP-1 cells with serum reduced C3b/iC3b deposition. Overall, our data indicate that apoE and FH interact with monocytic cells in a concerted action and this interaction reduces complement activation and inflammation in the atherosclerotic lesions. By this way FH may participate in mediating the beneficial effects of apoE in suppressing atherosclerotic lesion progression.
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Affiliation(s)
- Eija Nissilä
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Pipsa Hakala
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Katarzyna Leskinen
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Angela Roig
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Shahan Syed
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | | | - Jari Metso
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Carla J. C. De Haas
- Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Päivi Saavalainen
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Seppo Meri
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Angeliki Chroni
- Institute of Biosciences and Applications, National Center for Scientific Research “Demokritos”, Athens, Greece
| | | | | | - Matti Jauhiainen
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - T. Sakari Jokiranta
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
| | - Karita Haapasalo
- Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland
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Békássy ZD, Kristoffersson AC, Rebetz J, Tati R, Olin AI, Karpman D. Aliskiren inhibits renin-mediated complement activation. Kidney Int 2018; 94:689-700. [DOI: 10.1016/j.kint.2018.04.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 03/28/2018] [Accepted: 04/05/2018] [Indexed: 11/17/2022]
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48
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Abbas F, El Kossi M, Kim JJ, Sharma A, Halawa A. Thrombotic microangiopathy after renal transplantation: Current insights in de novo and recurrent disease. World J Transplant 2018; 8:122-141. [PMID: 30211021 PMCID: PMC6134269 DOI: 10.5500/wjt.v8.i5.122] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Revised: 06/26/2018] [Accepted: 07/10/2018] [Indexed: 02/05/2023] Open
Abstract
Thrombotic microangiopathy (TMA) is one of the most devastating sequalae of kidney transplantation. A number of published articles have covered either de novo or recurrent TMA in an isolated manner. We have, hereby, in this article endeavored to address both types of TMA in a comparative mode. We appreciate that de novo TMA is more common and its prognosis is poorer than recurrent TMA; the latter has a genetic background, with mutations that impact disease behavior and, consequently, allograft and patient survival. Post-transplant TMA can occur as a recurrence of the disease involving the native kidney or as de novo disease with no evidence of previous involvement before transplant. While atypical hemolytic uremic syndrome is a rare disease that results from complement dysregulation with alternative pathway overactivity, de novo TMA is a heterogenous set of various etiologies and constitutes the vast majority of post-transplant TMA cases. Management of both diseases varies from simple maneuvers, e.g., plasmapheresis, drug withdrawal or dose modification, to lifelong complement blockade, which is rather costly. Careful donor selection and proper recipient preparation, including complete genetic screening, would be a pragmatic approach. Novel therapies, e.g., purified products of the deficient genes, though promising in theory, are not yet of proven value.
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Affiliation(s)
- Fedaey Abbas
- Nephrology Department, Jaber El Ahmed Military Hospital, Safat 13005, Kuwait
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
| | - Mohsen El Kossi
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Doncaster Renal Unit, Doncaster Royal Infirmary, Doncaster DN2 5LT, United Kingdom
| | - Jon Jin Kim
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Nottingham Children Hospital, Nottingham NG7 2UH, United Kingdom
| | - Ajay Sharma
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Transplant Surgery, Royal Liverpool University Hospitals, Liverpool UK L7 8XP, United Kingdom
| | - Ahmed Halawa
- Faculty of Health and Science, University of Liverpool, Institute of Learning and Teaching, School of Medicine, Liverpool L69 3GB, United Kingdom
- Department of Transplantation Surgery, Sheffield Teaching Hospitals, Sheffield S57AU, United Kingdom
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49
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Vankalakunti M, Augustine R, Jangamani R, Siddini V, Bonu R, Babu K, Ballal SH. Dense Deposit Disease Involving C3 and C4d Deposits. Indian J Nephrol 2018. [PMID: 29515303 PMCID: PMC5830811 DOI: 10.4103/ijn.ijn_164_16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Dense deposit disease (DDD), earlier called Type II membranoproliferative glomerulonephritis is distinct disease having frequent relapses reaching end-stage kidney disease by 10-year in up to 50%-60% of cases and high recurrence rate in the allograft. The term DDD is derived from its distinctive ribbon-like osmiophilic deposits in the lamina densa of glomerular basement membrane by electron microscopy. Pathogenetically, alternate pathway dysfunction leads to this disease, which is diagnosed by ultrastructure. Herein, we describe our observation of C4d positivity in an adolescent boy with DDD.
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Affiliation(s)
- M Vankalakunti
- Department of Nephropathology, Manipal Hospital, Bengaluru, Karnataka, India
| | - R Augustine
- Department of Nephrology, Manipal Hospital, Bengaluru, Karnataka, India
| | - R Jangamani
- Department of Nephrology, Manipal Hospital, Bengaluru, Karnataka, India
| | - V Siddini
- Department of Nephrology, Manipal Hospital, Bengaluru, Karnataka, India
| | - R Bonu
- Department of Nephrology, Manipal Hospital, Bengaluru, Karnataka, India
| | - K Babu
- Department of Nephrology, Manipal Hospital, Bengaluru, Karnataka, India
| | - S H Ballal
- Department of Nephrology, Manipal Hospital, Bengaluru, Karnataka, India
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50
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Rudnick RB, Chen Q, Stea ED, Hartmann A, Papac-Milicevic N, Person F, Wiesener M, Binder CJ, Wiech T, Skerka C, Zipfel PF. FHR5 Binds to Laminins, Uses Separate C3b and Surface-Binding Sites, and Activates Complement on Malondialdehyde-Acetaldehyde Surfaces. THE JOURNAL OF IMMUNOLOGY 2018; 200:2280-2290. [PMID: 29483359 DOI: 10.4049/jimmunol.1701641] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 01/30/2018] [Indexed: 12/17/2022]
Abstract
Factor H related-protein 5 (CFHR5) is a surface-acting complement activator and variations in the CFHR5 gene are linked to CFHR glomerulonephritis. In this study, we show that FHR5 binds to laminin-521, the major constituent of the glomerular basement membrane, and to mesangial laminin-211. Furthermore, we identify malondialdehyde-acetaldehyde (MAA) epitopes, which are exposed on the surface of human necrotic cells (Homo sapiens), as new FHR5 ligands. Using a set of novel deletion fragments, we show that FHR5 binds to laminin-521, MAA epitopes, heparin, and human necrotic cells (HUVECs) via the middle region [short consensus repeats (SCRs) 5-7]. In contrast, surface-bound FHR5 contacts C3b via the C-terminal region (SCRs8-9). Thus, FHR5 uses separate domains for C3b binding and cell surface interaction. MAA epitopes serve as a complement-activating surface by recruiting FHR5. The complement activator FHR5 and the complement inhibitor factor H both bind to oxidation-specific MAA epitopes and FHR5 competes with factor H for binding. The C3 glomerulopathy-associated FHR21-2-FHR5 hybrid protein is more potent in MAA epitope binding and activation compared with wild-type FHR5. The implications of these results for pathology of CFHR glomerulonephritis are discussed. In conclusion, we identify laminins and oxidation-specific MAA epitopes as novel FHR5 ligands and show that the surface-binding site of FHR5 (SCRs5-7) is separated from the C3b binding site (SCRs8-9). Furthermore, FHR5 competes with factor H for binding to MAA epitopes and activates complement on these modified structures.
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Affiliation(s)
- Ramona B Rudnick
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany
| | - Qian Chen
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany
| | - Emma Diletta Stea
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany
| | - Andrea Hartmann
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany
| | - Nikolina Papac-Milicevic
- Clinical Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, 1090 Vienna, Austria.,Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
| | - Fermin Person
- Institute of Pathology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Michael Wiesener
- Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nuremberg, 91054 Erlangen, Germany; and
| | - Christoph J Binder
- Clinical Department of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, 1090 Vienna, Austria.,Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
| | - Thorsten Wiech
- Institute of Pathology, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Christine Skerka
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany
| | - Peter F Zipfel
- Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany; .,Department Microbiology, Friedrich-Schiller-University, 07745 Jena, Germany
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