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Duan ZY, Li JJ, Cai GY, Wang S, Tang X, Hou W, Jiang L, Song Y. C3 glomerulopathy associated with mycoplasma pneumoniae infection and positive IgA staining. BMC Nephrol 2025; 26:85. [PMID: 39966764 PMCID: PMC11837633 DOI: 10.1186/s12882-025-04010-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 02/05/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Patients with C3 glomerulopathy (C3G) often have a history of infection, which implies that infection may lead to abnormal activation of the complement alternative pathway (CAP) and induce the development of C3G. However, patients with postinfectious glomerulonephritis (PIGN) often have a low serum C3 concentration and positive glomerular C3 staining, consistent with the activation of the CAP. PIGN, especially if it involves simultaneous IgA deposition, is often difficult to differentiate from C3G. CASE PRESENTATION In this study, we report the consequences of Mycoplasma pneumoniae (MP) infection in a 66-year-old male Chinese patient, who developed persistent hypocomplementemia, gross hematuria, and rapidly progressive glomerulonephritis. The findings of the histologic examination of an initial renal biopsy were consistent with a diagnosis of IgA-dominant postinfectious glomerulonephritis. The sample was negative for Gd-IgA1 staining. After treatment with antibiotics, glucocorticoids, and mycophenolate mofetil, the patient's serum creatinine decreased from a peak of 387 µmol/L to 195 µmol/L prior to discharge, and there was a partial response in his urinary protein concentration. After 2 months, his serum C3 concentration had returned to normal. However, owing to reinfection with MP the patient's serum creatinine rapidly increased again to 475.07 µmol/L, and this was accompanied by a decrease in serum C3 concentration (> 8 months) and positivity for C3 nephritis factor. Examination of both renal biopsies showed stronger immunostaining for C3 than for IgA in the glomeruli. CONCLUSION Thus, MP infection can cause sustained activation of the CAP, leading to C3G. For patients with MP infection, if there is an ongoing decrease in complement C3 levels and a progressive increase in serum creatinine, it is crucial to be vigilant for possible C3G and to consider the use of immunosuppressive therapy in conjunction with anti-infective treatment to prevent the ongoing activation of the CAP.
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Affiliation(s)
- Zhi-Yu Duan
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, Beijing, 100853, China
| | - Ji-Jun Li
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, Beijing, 100853, China
| | - Guang-Yan Cai
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, Beijing, 100853, China
| | - SuXia Wang
- Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, 100034, China
| | - XuanLi Tang
- Department of Nephrology (Key Laboratory of Kidney Disease Prevention and Control Technology), Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310007, China
| | - WanYin Hou
- Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, 100034, China
| | - Lei Jiang
- Renal Division, Department of Medicine, Institute of Nephrology, Peking University First Hospital, Peking University, Beijing, 100034, China
| | - Yan Song
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, National Key Laboratory of Kidney Diseases, Beijing Key Laboratory of Kidney Diseases Research, National Clinical Research Center for Kidney Diseases, Beijing, 100853, China.
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Guzman GL, Perry KW. Pegcetacoplan for the Treatment of Paediatric C3 Glomerulonephritis: A Case Report. Nephrology (Carlton) 2025; 30:e70001. [PMID: 39871447 PMCID: PMC11772912 DOI: 10.1111/nep.70001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 12/03/2024] [Accepted: 01/17/2025] [Indexed: 01/29/2025]
Abstract
Complement 3 glomerulonephritis (C3GN) is a rare glomerular disease involving dysregulation of the complement system. We describe our experience using pegcetacoplan, an inhibitor of C3 and its activation fragment, C3b, for treatment-resistant C3GN in a 9-year-old boy referred for evaluation of refractory membranoproliferative glomerulonephritis. Despite treatment with intense immunosuppression (high-dose steroids, mycophenolate mofetil and calcineurin inhibitor), he continued to have high disease activity with low C3 levels (35 mg/dL), hypertension, symptomatic oedema, anaemia, and nephrotic-range proteinuria (e.g., urine protein-to-creatinine ratio [uPCR], 10 g/g; serum creatinine, 0.4 mg/dL). Given the concern for refractory C3GN following a steroid taper and tacrolimus trial with modest response (reduced proteinuria), we initiated pegcetacoplan 540 mg twice weekly for 1 week, followed by 648 mg twice weekly. Laboratory values before pegcetacoplan initiation included uPCR, 1.1 g/g, serum creatinine, 0.87 mg/dL, serum albumin, 4.7 g/dL, and serum C3, 30 mg/dL. Clinically significant improvements in serum C3 (142 mg/dL) and uPCR (422 mg/g) were observed within 1 week of pegcetacoplan initiation; within 3 months (uPCR, 322 mg/g; serum creatinine, 0.69 mg/dL; serum C3, 297 mg/dL), all immunosuppressive and antihypertensive medications were discontinued. No adverse effects of pegcetacoplan were reported. A kidney biopsy after 6 months of pegcetacoplan treatment showed mesangial and focal endocapillary proliferative glomerulonephritis with isolated C3c deposition by immunofluorescence, consistent with previous C3GN diagnosis. In this paediatric patient, compassionate use of pegcetacoplan was associated with rapid clinical improvement without adverse effects, and clinical effectiveness was confirmed by laboratory and histologic results within 6 months of treatment initiation.
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Roquigny J, Meuleman MS, el Sissy C, Cailliez M, Servais A, Roussey G, Baudouin V, Decramer S, Nobili F, Wynckel A, Sellier Leclerc AL, Lapeyraque AL, Martins PV, Meri S, Dragon-Durey MA, Chauvet S, Frémeaux-Bacchi V. Functional Characterization of Anti-C3bBb Autoantibodies and C3 Glomerulopathy Phenotype. J Am Soc Nephrol 2025; 36:264-273. [PMID: 39325562 PMCID: PMC11801764 DOI: 10.1681/asn.0000000000000499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 09/23/2024] [Indexed: 09/28/2024] Open
Abstract
Key Points Dysregulation of the C3bBb convertase is a key factor in the pathogenesis of C3 glomerulopathy and primary Ig-mediated membranoproliferative GN. IgG-driven increase of the C3bBb convertase formation was correlated with C3 consumption. IgG antibodies that promote the formation and the stabilization of the C3bBb convertase were associated with the severity of C3 glomerulopathy. Background C3 nephritic factors, that is, autoantibodies that stabilize the C3 convertase of the alternative pathway are the most frequent acquired abnormality in C3 glomerulopathy and primary Ig-mediated membranoproliferative GN (Ig-MPGN). Methods Our study included 27 patients with C3 glomerulopathy (n =21) or Ig-MPGN (n =6), of whom 78% were children at disease onset. At the time of sampling, 13/19 patients (68%) with low C3 levels and 8/8 patients (100%) with normal C3 levels were positive for C3 nephritic factors by hemolytic assay. Using novel Luminex assays, we performed a screening for IgG that recognize and affect the formation and/or the stabilization of the alternative pathway C3 convertase (C3bBb). Results Using Luminex assays, an increase in C3bBb formation and/or stabilization was observed in the presence of IgG from 18/27 patients, including nine with a double-function, six only enhancing the C3bBb formation, and three that exclusively stabilized C3bBb. All patients presenting a formation and stabilization function had a low C3 level versus 55% without this double-function. The level of C3bBb formation correlated to the plasmatic C3 but not soluble C5b-9 levels. The stabilization of C3bBb did not correlate with C3 or soluble C5b-9 levels. At the last follow-up, 5/27 patients (19%) reached kidney failure after a median delay of 87 (52–119) months. The patients positive for double-function anti-C3bBb antibodies had a 5-year kidney survival of 70% compared with 100% in those negative (P = 0.02). Conclusions Our findings highlight the association of the dual function of C3bBb formation and stabilization with severe C3 consumption and poor kidney survival in C3 glomerulopathy and Ig-MPGN.
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Affiliation(s)
- Julia Roquigny
- Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France
- Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
| | - Marie-Sophie Meuleman
- Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France
| | - Carine el Sissy
- Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France
- Department of Immunology, Assistance Publique - Hôpitaux de Paris (AP-HP), Georges Pompidou European Hospital, Paris, France
| | - Mathilde Cailliez
- Department of Pediatric Nephrology, Marseille University Hospital, Marseille, France
| | - Aude Servais
- Department of Nephrology, Necker Hospital, Paris, France
| | - Gwenaelle Roussey
- Department of Pediatric Nephrology, Nantes University Hospital, Nantes, France
| | - Véronique Baudouin
- Department of Pediatric Nephrology, Robert Debre Hospital, Paris, France
| | - Stéphane Decramer
- Department of Nephrology, Toulouse University Hospital, Toulouse, France
| | - François Nobili
- Department of Nephrology, Besancon University Hospital, Besancon, France
| | - Alain Wynckel
- Department of Nephrology, Reims University Hospital, Reims, France
| | | | | | - Paula Vieira Martins
- Department of Immunology, Assistance Publique - Hôpitaux de Paris (AP-HP), Georges Pompidou European Hospital, Paris, France
| | - Seppo Meri
- Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland
| | - Marie-Agnès Dragon-Durey
- Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France
- Department of Immunology, Assistance Publique - Hôpitaux de Paris (AP-HP), Georges Pompidou European Hospital, Paris, France
| | - Sophie Chauvet
- Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France
- Department of Nephrology, Assistance Publique - Hôpitaux de Paris (AP-HP), Georges Pompidou European Hospital, Paris, France
| | - Véronique Frémeaux-Bacchi
- Inflammation, Complement and Cancer Team, Cordeliers Research Center, Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) S1138, Paris, France
- Department of Immunology, Assistance Publique - Hôpitaux de Paris (AP-HP), Georges Pompidou European Hospital, Paris, France
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Sato S, Miwa T, Gullipalli D, Golla M, Mohammadyari E, Zhou L, Palmer M, Song WC. Improved therapeutic efficacy of a bifunctional anti-C5 mAb-FH SCR1-5 fusion protein over anti-C5 mAb in an accelerated mouse model of C3 glomerulopathy. Immunohorizons 2025; 9:vlae006. [PMID: 39865974 PMCID: PMC11841979 DOI: 10.1093/immhor/vlae006] [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: 10/23/2024] [Accepted: 10/23/2024] [Indexed: 01/28/2025] Open
Abstract
C3 glomerulopathy (C3G), a rare kidney disease caused by dysregulation of alternative pathway complement activation, is characterized by glomerular C3 deposition, proteinuria, crescentic glomerulonephritis, and renal failure. The anti-C5 monoclonal antibody (mAb) drug eculizumab has shown therapeutic effects in some but not all patients with C3G, and no approved therapy is currently available. Here, we developed and used a triple transgenic mouse model of fast progressing lethal C3G (FHm/mP-/-hFDKI/KI) to compare the therapeutic efficacy of a bifunctional anti-C5 mAb fused to a functional factor H (FH) fragment (short consensus repeat 1-5 [SCR1-5]) and the anti-C5 mAb itself. The new C3G mouse model is derived by humanizing factor D (hFDKI/KI) in a previously described FHm/mP-/- mouse that developed lethal C3G. We tested the effectiveness of these 2 complement inhibitors in triple transgenic mice with established C3G and glomerular disease. No FHm/mP-/-hFDKI/KI mice treated with vehicle survived the 30-d study period. All FHm/mP-/-hFDKI/KI mice treated with the C5 mAb-FH SCR1-5 fusion protein and 50% of mice treated with the anti-C5 mAb survived the 30-d treatment period. Moreover, mice treated with the C5 mAb-FH SCR1-5 fusion protein, but not those treated with the anti-C5 mAb, showed restored plasma alternative pathway complement control. The C5 mAb-FH SCR1-5 fusion protein reversed glomerular disease to a greater degree than the anti-C5 mAb. These data suggest that simultaneously inhibiting the terminal and proximal complement pathways, by anti-C5 mAb and FH SCR1-5, respectively, can reverse established C3G and is more efficacious than inhibiting the terminal pathway alone. A similar approach may be effective in treating human C3G.
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Affiliation(s)
- Sayaka Sato
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Takashi Miwa
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Damodar Gullipalli
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Madhu Golla
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Eshagh Mohammadyari
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Lin Zhou
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Matthew Palmer
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Wen-Chao Song
- Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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Bomback AS, Charu V, Fakhouri F. Challenges in the Diagnosis and Management of Immune Complex-Mediated Membranoproliferative Glomerulonephritis and Complement 3 Glomerulopathy. Kidney Int Rep 2025; 10:17-28. [PMID: 39810761 PMCID: PMC11725974 DOI: 10.1016/j.ekir.2024.09.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 09/13/2024] [Accepted: 09/17/2024] [Indexed: 01/16/2025] Open
Abstract
Immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and complement 3 glomerulopathy (C3G) are rare, complement-mediated kidney diseases, previously classified under the group of kidney disorders termed membranoproliferative glomerulonephritis (MPGN) type 1, type 2, and type 3. Despite new advances in our understanding of IC-MPGN and C3G, several unmet needs persist in the diagnosis and management of patients with these nephropathies, due in part to their rarity and their overlapping clinical presentations, histologic features, and underlying pathophysiologies. This review summarizes our current understanding of the role of complement in IC-MPGN and C3G, and underlines the key histopathologic differences between the diseases. Using seven illustrative patient cases, we discuss consensus guideline treatment recommendations and the uncertainties, challenges, and considerations regarding the diagnosis and management of patients with IC-MPGN and C3G in clinical practice. The presented cases emphasize the need for a multidisciplinary approach encompassing primary care providers (PCPs), nephrologists, nephropathologists, and laboratory scientists. Key knowledge gaps are evaluated, including differential diagnoses, underlying pathologic mechanisms, and the lack of effective treatments targeting drivers of disease. As the therapeutic landscape evolves, an improved understanding of IC-MPGN and C3G is crucial to identifying optimal targeted-treatment strategies and facilitating a personalized approach to the management of these complex glomerular diseases.
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Affiliation(s)
- Andrew S. Bomback
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Vivek Charu
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Fadi Fakhouri
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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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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Beirão B, Freitas M, Silva N, Ferraz P, Prata C, Morgado T. C3 glomerulonephritis associated with monoclonal gammopathy of renal significance: a diagnostic and therapeutic challenge. J Bras Nefrol 2024; 46:e20240092. [PMID: 39284028 PMCID: PMC11542637 DOI: 10.1590/2175-8239-jbn-2024-0092en] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 07/26/2024] [Indexed: 11/09/2024] Open
Affiliation(s)
- Bárbara Beirão
- Centro Hospitalar de Trás-os-Montes e Alto Douro, Hospital de Vila Real, Serviço de Nefrologia, Vila Real, Portugal
| | - Mariana Freitas
- Centro Hospitalar de Trás-os-Montes e Alto Douro, Hospital de Vila Real, Serviço de Nefrologia, Vila Real, Portugal
| | - Natália Silva
- Centro Hospitalar de Trás-os-Montes e Alto Douro, Hospital de Vila Real, Serviço de Nefrologia, Vila Real, Portugal
| | - Patrícia Ferraz
- Centro Hospitalar de Trás-os-Montes e Alto Douro, Hospital de Vila Real, Serviço de Hematologia Clínica, Vila Real, Portugal
| | - Catarina Prata
- Centro Hospitalar de Trás-os-Montes e Alto Douro, Hospital de Vila Real, Serviço de Nefrologia, Vila Real, Portugal
| | - Teresa Morgado
- Centro Hospitalar de Trás-os-Montes e Alto Douro, Hospital de Vila Real, Serviço de Nefrologia, Vila Real, Portugal
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Nayak PP, Pradhan P, Pradhan D, Mohapatra N, Raman S, Sahoo P. To interpret and analyze the changing patterns of histology and direct immunofluorescence findings in membranoproliferative glomerulonephritis. INDIAN J PATHOL MICR 2024; 67:80-85. [PMID: 38358193 DOI: 10.4103/ijpm.ijpm_1015_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024] Open
Abstract
Background Membranoproliferative glomerulonephritis has in the recent past been regrouped into immune complex-mediated (ICM MPGN) disease (driven by the classical complement pathway) and complement-mediated (C3GN) disease (driven by the alternative complement pathway) based on pathogenetic role of alternative complement pathway and immunofluorescence deposits. The proposed regrouping lent therapeutic and prognostic support in managing the disease of MPGN. Aims and Objectives The present study is undertaken to study the patterns of MPGN based on histopathological and DIF examination and sub-categorize the cases into mainly complement dominant and immune complex-mediated diseases for better prognostic and therapeutic utility. Materials and Methods This is a prospective observational study carried out in a tertiary care center over a period of 2 yrs. The clinically suspected cases of MPGN were subjected to histopathologic and direct immunofluorescence examination (DIF), and the findings were interpreted in light of complement-mediated and immune complex-mediated MPGN. Results Out of 620 renal biopsies, diagnosis of MPGN was confirmed both on histopathology and DIF in 36 cases accounting for 5.8% of all biopsies. Based on DIF findings, the various groups comprised 20 cases (55.6%) of immune complex deposits, 11 (30.5%) of C3 dominant picture, and 5 (13.9%) of Nil immune deposits. On analysis of the patterns on DIF, 16 cases (80%) of C3 + Ig group and 6 (54.5%) of C3GN group showed predominantly MPGN pattern. Crescentic glomerulonephritis, global glomerulosclerosis, and interstitial fibrosis were markedly observed in C3GN group. Conclusion DIF is of immense prognostic and therapeutic value in managing cases of MPGN.
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Affiliation(s)
- Pragnya P Nayak
- Department of Patholgy, Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
| | - Pranati Pradhan
- Department of Patholgy, Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
| | - Dilleswari Pradhan
- Department of Patholgy, Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
| | - Nachiketa Mohapatra
- Department of Patholgy, Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
| | - Sarojini Raman
- Department of Patholgy, Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
| | - Pranabandhu Sahoo
- Department of Patholgy, Srirama Chandra Bhanja Medical College, Cuttack, Odisha, India
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Goto K, Imaizumi T, Hamada R, Ishikura K, Kosugi T, Narita I, Sugiyama H, Shimizu A, Yokoyama H, Sato H, Mauryama S. Renal pathology in adult and paediatric population of Japan: review of the Japan renal biopsy registry database from 2007 to 2017. J Nephrol 2023; 36:2257-2267. [PMID: 37597092 PMCID: PMC10638177 DOI: 10.1007/s40620-023-01687-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 05/17/2023] [Indexed: 08/21/2023]
Abstract
BACKGROUND The Japan Renal Biopsy Registry (J-RBR), a nationwide, web-based, registry system, started in 2007. This study aimed to summarise the epidemiology of biopsy-diagnosed kidney disease in Japan over 10 years. METHODS We analysed the J-RBR database, from 2007 to 2017. Patients' clinical data collected at the time of biopsy and histopathological diagnoses were used for epidemiological and clinicopathologic analyses. RESULTS The predominant renal biopsy diagnoses were immunoglobulin A nephropathy (39.2%), lupus nephritis (6.5%) and minimal change disease (6.0%) in younger adults (19-64 years), and membranous nephropathy (17.4%), antineutrophil cytoplasmic antibody-associated vasculitis or anti-glomerular basement membrane glomerulonephritis (13.0%), and immunoglobulin A nephropathy (12.5%) in older adults (≥ 65 years). The percentages of patients diagnosed with membranoproliferative glomerulonephritis and immunoglobulin A nephropathy decreased, whereas those with immunoglobulin A vasculitis and diabetic nephropathy increased over the decade. In paediatric patients (< 19 years), immunoglobulin A nephropathy (36.1%), minimal change disease (17.6%), and immunoglobulin A vasculitis (8.6%) were the predominant diagnoses. The percentage of patients diagnosed with immunoglobulin A vasculitis increased over the decade. Based on the sex distribution, minimal change disease and membranous nephropathy were predominant in men aged < 20 and > 40 years, respectively, whereas immunoglobulin A vasculitis and antineutrophil cytoplasmic antibody-associated vasculitis or anti-glomerular basement membrane glomerulonephritis were predominant in women in their 20s and 30s and aged < 50 years, respectively. Immunoglobulin A nephropathy was predominant in men at most ages and in women in their 20s to 40s. CONCLUSIONS This study describes the distribution and changes in kidney biopsy diagnoses over 10 years in Japan and paves the way for future research on kidney diseases in adults and children.
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Affiliation(s)
- Kazunori Goto
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Takahiro Imaizumi
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
- Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Riku Hamada
- Department of Nephrology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
| | - Kenji Ishikura
- Department of Pediatrics, Kitasato University School of Medicine, Kanagawa, Japan
| | - Tomoki Kosugi
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Ichiei Narita
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hitoshi Sugiyama
- Department of Medicine, Kawasaki Medical School General Medical Center, Okayama, Japan
- Department of Medical Care Work, Kawasaki College of Allied Health Professions, Okayama, Japan
| | - Akira Shimizu
- Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan
| | - Hitoshi Yokoyama
- Department of Nephrology, Kanazawa Medical University School of Medicine, Ishikawa, Japan
| | | | - Shoichi Mauryama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
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10
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Ekladious A, Bhandari R, Javaid MM. Association of monoclonal gammopathy of undetermined significance and C3 glomerulopathy. Intern Med J 2023; 53:1712-1715. [PMID: 37665716 DOI: 10.1111/imj.16222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 07/12/2023] [Indexed: 09/06/2023]
Abstract
Monoclonal gammopathy of undetermined significance (MGUS) is usually an asymptomatic pre-malignant condition caused by the proliferation of clonal plasma cells. Often considered a benign condition, it has the potential to progress to malignant plasma cell or lymphoproliferative disorders. Moreover, MGUS can rarely cause glomerular disease by activating the alternative complement pathway resulting in immunoglobulin-negative C3-positive glomerulonephritis called C3 glomerulopathy. Because of its rarity, the diagnosis might not be considered by the treating physicians, leading to delayed diagnosis or misdiagnosis. Untreated C3 glomerulopathy can lead to irreversible glomerular damage and end-stage renal failure, and a high index of suspicion is essential for timely diagnosis and management. Here, we present the case of a patient with a prior diagnosis of MGUS who presented with proteinuria and microscopic haematuria and was diagnosed with C3 glomerulopathy. The patient had complete resolution of the disease after receiving treatment with a combination of dexamethasone, lenalidomide and bortezomib for the underlying MGUS.
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Affiliation(s)
- Adel Ekladious
- Department of General Medicine and Acute Assessment Unit, Canberra Hospital, Canberra, Australian Capital Territory, Australia
- Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia
| | - Ritesh Bhandari
- Department of General Medicine, Royal Hobart Hospital, Hobart, Tasmania, Australia
| | - Muhammad M Javaid
- Department of Renal Medicine, Woodlands Health, Singapore, Singapore
- School of Medicine, Monash University, Melbourne, Victoria, Australia
- School of Medicine, Deakin University, Burwood, Victoria, Australia
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11
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Bruck H, von Kiel C. [Autoimmune diagnostics in nephrology and rheumatology]. Dtsch Med Wochenschr 2023; 148:230-240. [PMID: 36848886 DOI: 10.1055/a-1844-9568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
Abstract
Autoimmune diagnostics plays a central role in the detection of various acute and/or chronic diseases in both nephrology and rheumatology, which are associated with high morbidity and mortality if left untreated or not detected in time. Patients are threatened with significant limitations in everyday skills and quality of life due to loss of kidney function and dialysis, immobilizing and destructive joint processes or also significant damage of organ systems. In all of these autoimmune diseases, early diagnosis and treatment is of central importance for the further course and prognosis of disease.Antibodies play an essential role in the pathogenesis of autoimmune diseases. Antibodies are either directed against organ or tissue-specific antigens, such as in primary membranous glomerulonephritis or Goodpasture's syndrome, or they lead to a systemic disease such as systemic lupus erythematosus (SLE) or rheumatoid arthritis.Knowledge of the sensitivity and specificity of antibodies is crucial for the interpretation of antibody diagnostics results. Antibody detection can precede the clinical onset of the disease, and antibody titers often reflect disease activity. However, there are also false positive results. Detection of antibodies in the absence of disease symptoms often leads to uncertainty and unnecessary further diagnostics. Therefore, an unfounded "antibody screening" is not recommended.A rational antibody diagnostics is an integral part of the diagnostics and during treatment of nephrological and rheumatological diseases like glomerulonephrititis, pulmorenal syndrome, SLE and other collagenosis, thrombotic microangiopathy (HUS/TTP) and rheumatoid arthritis.
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12
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Ding X, Qamar A, Liu H. The complement system testing in clinical laboratory. Clin Chim Acta 2023; 541:117238. [PMID: 36746263 DOI: 10.1016/j.cca.2023.117238] [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: 11/24/2022] [Revised: 01/24/2023] [Accepted: 01/25/2023] [Indexed: 02/07/2023]
Abstract
With the advancement in research in the field of the complement system, a more comprehensive understanding developed about the complement system's role in the life process of an organism. It is a system of innate immune surveillance. This system plays a pivotal role in host defense against pathogens, inflammation, B and T cell homeostasis. Complement system analysis has a significant advantage in the assessment of the immune system status, diagnosis and prognosis of diseases, and medication guidelines. Currently, complement system testing is neither yet widely used across all clinical laboratoriesnor are the testing protocols yet systematic. Based on the current research, it is suggested that the analysis of complement activator-activated complement activity and total complement activity would be comprehensively assessed to evaluate the complement system's immunological function, and combine of the detection of its components to establish a systematic protocol for the complement system testing in the clinical laboratory. This article reviews the complement system's physiological role, disease relevance and the current testing status in clinical laboratories. Further more, some suggestions have also been provided for the preparation of complement standards i.e., the standardized preparation process for complement standards seems to be a feasible option given the easy inactivation of complement.
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Affiliation(s)
- Xuewei Ding
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China
| | - Ayub Qamar
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China
| | - Hui Liu
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China.
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13
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Schubart A, Flohr S, Junt T, Eder J. Low-molecular weight inhibitors of the alternative complement pathway. Immunol Rev 2023; 313:339-357. [PMID: 36217774 PMCID: PMC10092480 DOI: 10.1111/imr.13143] [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] [Indexed: 01/20/2023]
Abstract
Dysregulation of the alternative complement pathway predisposes individuals to a number of diseases. It can either be evoked by genetic alterations in or by stabilizing antibodies to important pathway components and typically leads to severe diseases such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, C3 glomerulopathy, and age-related macular degeneration. In addition, the alternative pathway may also be involved in many other diseases where its amplifying function for all complement pathways might play a role. To identify specific alternative pathway inhibitors that qualify as therapeutics for these diseases, drug discovery efforts have focused on the two central proteases of the pathway, factor B and factor D. Although drug discovery has been challenging for a number of reasons, potent and selective low-molecular weight (LMW) oral inhibitors have now been discovered for both proteases and several molecules are in clinical development for multiple complement-mediated diseases. While the clinical development of these inhibitors initially focuses on diseases with systemic and/or peripheral tissue complement activation, the availability of LMW inhibitors may also open up the prospect of inhibiting complement in the central nervous system where its activation may also play an important role in several neurodegenerative diseases.
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Affiliation(s)
- Anna Schubart
- Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Stefanie Flohr
- Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Tobias Junt
- Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Jörg Eder
- Novartis Institutes for BioMedical Research, Basel, Switzerland
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14
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Ryu J, Baek E, Son HE, Ryu JY, Jeong JC, Kim S, Na KY, Chae DW, Kim SP, Kim SH, Jhee JH, Chang TI, Choi BS, Chin HJ. Comparison of dominant and nondominant C3 deposition in primary glomerulonephritis. Kidney Res Clin Pract 2023; 42:98-108. [PMID: 36747358 PMCID: PMC9902730 DOI: 10.23876/j.krcp.22.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 10/19/2022] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Alternative complement pathway dysregulation plays a key role in glomerulonephritis (GN) and is associated with C3 deposition. Herein, we examined pathological and clinical differences between cases of primary GN with C3-dominant (C3D-GN) and nondominant (C3ND-GN) deposition. METHODS We extracted primary GN data from the Korean GlomeruloNEphritis sTudy (KoGNET). C3D-GN was defined as C3 staining two grades greater than C1q, C4, and immunoglobulin via immunofluorescence analysis. To overcome a large difference in the number of patients between the C3D-GN and C3ND-GN groups (31 vs. 9,689), permutation testing was used for analysis. RESULTS The C3D-GN group exhibited higher serum creatinine (p ≤ 0.001), a greater prevalence of estimated glomerular filtration rate of <60 mL/min/1.72 m2 (p ≤ 0.001), higher (but not significantly so) C-reactive protein level, and lower serum C3 level (p ≤ 0.001). Serum albumin, urine protein/creatinine ratio, number of patients who progressed to end-stage renal disease, and all-cause mortality were comparable between groups. Interstitial fibrosis and mesangial cellularity were greater in the C3D-GN group (p = 0.04 and p = 0.01, respectively) than in the C3ND-GN group. C3 deposition was dominant in the former group (p < 0.001), in parallel with increased subendothelial deposition (p ≤ 0.001). CONCLUSION Greater progression of renal injury and higher mortality occurred in patients with C3D-GN than with C3ND-GN, along with pathologic differences in interstitial and mesangial changes.
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Affiliation(s)
- Jiwon Ryu
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Eunji Baek
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Hyung-Eun Son
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Ji-Young Ryu
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Jong Cheol Jeong
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea,Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea
| | - Sejoong Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea,Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea
| | - Ki Young Na
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea,Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea
| | - Dong-Wan Chae
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea,Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea
| | - Seong Pyo Kim
- Interdisciplinary Program of Medical Informatics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Su Hwan Kim
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jong Hyun Jhee
- Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Tae Ik Chang
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea
| | - Bum Soon Choi
- Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ho Jun Chin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea,Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea,Correspondence: Ho Jun Chin Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Republic of Korea. E-mail:
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15
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Zito A, De Pascalis A, Montinaro V, Ria P, Carbonara MC, Ferramosca E, Napoli M. Successful treatment of infectious endocarditis-associated glomerulonephritis during active hepatitis C infection: a case report. BMC Nephrol 2022; 23:390. [PMID: 36476330 PMCID: PMC9730680 DOI: 10.1186/s12882-022-02985-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 10/24/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Hepatitis C virus (HCV) may play a pathogenic role in several forms of immune complex glomerulonephritis (GN). We present a patient whose initial clinical presentation instilled suspicion of HCV-related renal involvement. Yet, histopathologic data oriented towards a different diagnosis. CASE PRESENTATION A 68-year old man presented with kidney dysfunction, cryoglobulins, low C4 level, high HCV-RNA and cutaneous vasculitis. The first hypothesis was a hepatitis C-related cryoglobulinemic glomerulonephritis. Renal biopsy revealed endocapillary and mesangial cells hypercellularity with complement C3 and IgM deposits. The echocardiography showed an infectious endocarditis (IE) on aortic valve. Appropriate antibiotic therapy and a prosthetic valve replacement were performed, obtaining recovery of renal function. CONCLUSION HCV infection may be linked to multiple renal manifestations, often immune-complex GN such as cryoglobulinemic membrano-proliferative GN. Renal disease due to IE is usually associated to focal, segmental or diffuse proliferative GN, with prominent endocapillary proliferation. The most common infectious agents are Staphylococcus aureus and Streptococcus species. This case report may be relevant because the renal dysfunction was highly suggestive of a cryoglobulinemic GN on a clinical ground, but the histologic pattern after performing the renal biopsy oriented towards a different cause of the underlying disease, that required a specific antibiotic treatment. The renal biopsy is always required to confirm a clinical suspicious in patients affected by multiple comorbidities.
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Affiliation(s)
- Anna Zito
- grid.417011.20000 0004 1769 6825Department of Nephrology, Vito Fazzi Hospital, Lecce, Italy
| | - Antonio De Pascalis
- grid.417011.20000 0004 1769 6825Department of Nephrology, Vito Fazzi Hospital, Lecce, Italy
| | - Vincenzo Montinaro
- grid.415987.60000 0004 1758 8613Department of Nephrology, Miulli General Hospital, Acquaviva delle Fonti, Bari, Italy
| | - Paolo Ria
- grid.417011.20000 0004 1769 6825Department of Nephrology, Vito Fazzi Hospital, Lecce, Italy
| | | | - Emiliana Ferramosca
- grid.417011.20000 0004 1769 6825Department of Nephrology, Vito Fazzi Hospital, Lecce, Italy
| | - Marcello Napoli
- grid.417011.20000 0004 1769 6825Department of Nephrology, Vito Fazzi Hospital, Lecce, Italy
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16
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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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17
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Fakhouri F, Schwotzer N, Golshayan D, Frémeaux-Bacchi V. The Rational Use of Complement Inhibitors in Kidney Diseases. Kidney Int Rep 2022; 7:1165-1178. [PMID: 35685323 PMCID: PMC9171628 DOI: 10.1016/j.ekir.2022.02.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/15/2022] [Accepted: 02/21/2022] [Indexed: 12/14/2022] Open
Abstract
The development of complement inhibitors represented one of the major breakthroughs in clinical nephrology in the last decade. Complement inhibition has dramatically transformed the outcome of one of the most severe kidney diseases, the atypical hemolytic uremic syndrome (aHUS), a prototypic complement-mediated disorder. The availability of complement inhibitors has also opened new promising perspectives for the management of several other kidney diseases in which complement activation is involved to a variable extent. With the rapidly growing number of complement inhibitors tested in a rapidly increasing number of indications, a rational use of this innovative and expensive new therapeutic class has become crucial. The present review aims to summarize what we know, and what we still ignore, regarding complement activation and therapeutic inhibition in kidney diseases. It also provides some clues and elements of thoughts for a rational approach of complement modulation in kidney diseases.
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Affiliation(s)
- Fadi Fakhouri
- Service de Néphrologie et d'hypertension, Département de Médecine, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne, Lausanne, Switzerland
| | - Nora Schwotzer
- Service de Néphrologie et d'hypertension, Département de Médecine, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne, Lausanne, Switzerland
| | - Déla Golshayan
- Centre de Transplantation d'organes, Département de Médecine, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne, Lausanne, Switzerland
| | - Véronique Frémeaux-Bacchi
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie, Paris University, Paris, France
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18
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Hou J, Ren KYM, Haas M. C3 Glomerulopathy: A Review with Emphasis on Ultrastructural Features. GLOMERULAR DISEASES 2022; 2:107-120. [PMID: 36751667 PMCID: PMC9710331 DOI: 10.1159/000524552] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/20/2022] [Indexed: 11/19/2022]
Abstract
C3 glomerulopathy (C3G) is a rare disease resulting from dysregulation of the alternative complement pathway, resulting in the deposition of complement component 3 (C3) in the kidney. It encompasses two major subgroups: dense deposit disease and C3 glomerulonephritis (C3GN). Although the alternative complement pathway is typically a very tightly controlled system, dysregulation can be a result of genetic mutations in the fluid phase or membrane-bound inhibitors or accelerators. In addition, de novo/acquired autoantibodies against any of the regulatory proteins can alter complement activation either by negating an inhibitor or activating an accelerator. Triggering events can be complex; however, the final pathway is characterized by the uncontrolled deposition of C3 in glomeruli and the formation of the membrane attack complex. Light microscopic findings can be quite heterogeneous with a membranoproliferative pattern most commonly encountered. Diagnostic confirmation of C3G is based on a characteristic pattern of glomerular immunofluorescence staining, with C3-dominant deposits that are at least 2 orders of intensity greater than staining for any immunoglobulin (Ig) or C1q. Electron microscopy is necessary for diagnosing DDD in particular, but can also help to distinguish C3GN from other glomerular disease mimickers.
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Affiliation(s)
- Jean Hou
- Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA
| | - Kevin Yi Mi Ren
- Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada
| | - Mark Haas
- Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA,*Mark Haas,
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19
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Mack HG, Colville DJ, Harraka P, Savige JA, Invernizzi A, Fraser-Bell S. Retinal findings in glomerulonephritis. Clin Exp Optom 2021; 105:474-486. [PMID: 34877922 DOI: 10.1080/08164622.2021.2003691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
The complement system is part of the innate immune system activated by three distinct pathways: classical, lectin and alternative. It is also involved in retinal development and homoeostasis. Dense deposit disease is a rare renal disease associated with mutations in Complement factor H and overactivity of the alternative complement pathway. As well as glomerulonephritis, many affected individuals have retinal drusen and may be at risk of vision loss due to macular atrophy or choroidal neovascularisation. We discuss the reclassification of dense deposit disease as a type of C3 glomerulonephropathy, and hypothesise on the mechanisms of retinal abnormalities. Drusen have also been described in individuals with other types of glomerulonephritis involving abnormalities of the classical (membranoproliferative glomerulonephritis type 1) or lectin (IgA nephropathy, lupus nephritis) complement pathways. Although drusen are found in abnormalities of all three complement pathways, the age at onset, aetiology, and the threat to vision differs. This review describes drusen and other retinal abnormalities associated with the glomerulonephritides due to abnormal activation in each of the three complement activation pathways, and provides the first report of drusen occurring in a patient with the recently reclassified C3 glomerulonephritis with homozygous variant V62I in complement factor H. Optometric management of young patients presenting with retinal drusen is discussed, and complement-based therapies for visual loss are reviewed.
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Affiliation(s)
- Heather G Mack
- Department of Surgery (Ophthalmology), University of Melbourne, Melbourne, Australia.,Department of Ophthalmology, Melbourne Health, Melbourne, Australia.,Centre for Eye Research, University of Melbourne, Melbourne, Australia
| | - Deborah J Colville
- Department of Surgery (Ophthalmology), University of Melbourne, Melbourne, Australia.,Department of Ophthalmology, Melbourne Health, Melbourne, Australia
| | - Phillip Harraka
- Department of Medicine (Northern), University of Melbourne, Melbourne, Australia
| | - Judith Anne Savige
- Department of Medicine (Northern), University of Melbourne, Melbourne, Australia
| | - Alessandro Invernizzi
- Department of Biomedical and Clinical Sciences 'Luigi Sacco', University of Milan, Milan, Italy
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20
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Johnson CK, Zuniga SC, Dhawale T, Zhang Y, Smith RJH, Blosser CD. Monoclonal Gammopathy of Renal Significance Causes C3 Glomerulonephritis Via Monoclonal IgG Kappa Inhibition of Complement Factor H. Kidney Int Rep 2021; 6:2505-2509. [PMID: 34514215 PMCID: PMC8418982 DOI: 10.1016/j.ekir.2021.06.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/10/2021] [Accepted: 06/14/2021] [Indexed: 11/29/2022] Open
Affiliation(s)
| | - Sandra Carias Zuniga
- Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
| | - Tejaswini Dhawale
- Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Yuzhou Zhang
- Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.,Departments of Internal Medicine and Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Richard J H Smith
- Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.,Departments of Internal Medicine and Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
| | - Christopher D Blosser
- Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.,Division of Nephrology, Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington, USA
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21
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Cara-Fuentes G, Smoyer WE. Biomarkers in pediatric glomerulonephritis and nephrotic syndrome. Pediatr Nephrol 2021; 36:2659-2673. [PMID: 33389089 DOI: 10.1007/s00467-020-04867-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/16/2020] [Accepted: 11/18/2020] [Indexed: 12/21/2022]
Abstract
Glomerular diseases are often chronic or recurring and thus associated with a tremendous physical, psychological, and economic burden. Their etiologies are often unknown, and their pathogeneses are frequently poorly understood. The diagnoses and management of these diseases are therefore based on clinical features, traditional laboratory markers, and, often, kidney pathology. However, the clinical presentation can be highly variable, the kidney pathology may not establish a definitive diagnosis, and the therapeutic responses and resulting clinical outcomes are often unpredictable. To try to address these challenges, significant research efforts have been made over the last decade to identify potential biomarkers that can help clinicians optimize the diagnosis and prognosis at clinical presentation, as well as help predict long-term outcomes. Unfortunately, these efforts have to date only identified a single biomarker for glomerular disease that has been fully validated and developed for widespread clinical use (anti-PLA2R antibodies to diagnose membranous nephropathy). In this manuscript, we review the definitions and development of biomarkers, as well as the current knowledge on both historical and novel candidate biomarkers of glomerular disease, with an emphasis on those associated with idiopathic nephrotic syndrome.
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Affiliation(s)
- Gabriel Cara-Fuentes
- Department of Pediatrics, Division of Pediatric Nephrology, University of Colorado, 12700 E 19th Ave, R2 building, Room 7420D, Aurora, CO, 80045, USA.
| | - William E Smoyer
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
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22
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Michels MAHM, van de Kar NCAJ, van Kraaij SAW, Sarlea SA, Gracchi V, Engels FAPT, Dorresteijn EM, van der Deure J, Duineveld C, Wetzels JFM, van den Heuvel LPWJ, Volokhina EB. Different Aspects of Classical Pathway Overactivation in Patients With C3 Glomerulopathy and Immune Complex-Mediated Membranoproliferative Glomerulonephritis. Front Immunol 2021; 12:715704. [PMID: 34456924 PMCID: PMC8386118 DOI: 10.3389/fimmu.2021.715704] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/20/2021] [Indexed: 11/13/2022] Open
Abstract
The rare and heterogeneous kidney disorder C3 glomerulopathy (C3G) is characterized by dysregulation of the alternative pathway (AP) of the complement system. C3G is often associated with autoantibodies stabilizing the AP C3 convertase named C3 nephritic factors (C3NeF). The role of classical pathway (CP) convertase stabilization in C3G and related diseases such as immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) remains largely unknown. Here, we investigated the CP convertase activity in patients with C3G and IC-MPGN. Using a refined two-step hemolytic assay, we measured the stability of CP convertases directly in the serum of 52 patients and 17 healthy controls. In four patients, CP convertase activity was prolonged compared to healthy controls, i.e. the enzymatic complex was stabilized. In three patients (2 C3G, 1 IC-MPGN) the convertase stabilization was caused by immunoglobulins, indicating the presence of autoantibodies named C4 nephritic factors (C4NeFs). Importantly, the assay also enabled detection of non-immunoglobulin-mediated stabilization of the CP convertase in one patient with C3G. Prolonged CP convertase activity coincided with C3NeF activity in all patients and for up to 70 months of observation. Crucially, experiments with C3-depleted serum showed that C4NeFs stabilized the CP C3 convertase (C4bC2a), that does not contain C3NeF epitopes. All patients with prolonged CP convertase activity showed clear signs of complement activation, i.e. lowered C3 and C5 levels and elevated levels of C3d, C3bc, C3bBbP, and C5b-9. In conclusion, this work provides new insights into the diverse aspects and (non-)immunoglobulin nature of factors causing CP convertase overactivity in C3G/IC-MPGN.
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Affiliation(s)
- Marloes A H M Michels
- Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands
| | - Nicole C A J van de Kar
- Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands
| | - Sanne A W van Kraaij
- Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
| | - Sebastian A Sarlea
- Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands
| | - Valentina Gracchi
- Department of Pediatric Nephrology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Flore A P T Engels
- Department of Pediatric Nephrology, Maastricht University Medical Center+, Maastricht, Netherlands
| | - Eiske M Dorresteijn
- Department of Pediatric Nephrology, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, Netherlands
| | | | - Caroline Duineveld
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Jack F M Wetzels
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Lambertus P W J van den Heuvel
- Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands.,Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.,Department of Pediatrics/Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium.,Department of Development and Regeneration, University Hospitals Leuven, Leuven, Belgium
| | - Elena B Volokhina
- Department of Pediatric Nephrology, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands.,Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
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23
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De Souza L, Prunster J, Chan D, Chakera A, Lim WH. Recurrent glomerulonephritis after kidney transplantation: a practical approach. Curr Opin Organ Transplant 2021; 26:360-380. [PMID: 34039882 DOI: 10.1097/mot.0000000000000887] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW This review will provide a practical approach in the assessment of kidney failure patients with primary glomerulonephritides (GN) being considered for kidney transplantation, focusing on high-risk subtypes of immunoglobulin A nephropathy, focal segmental glomerulosclerosis, idiopathic membranous glomerulonephritis and membranoproliferative glomerulonephritis. RECENT FINDINGS Recurrent glomerulonephritis remains one of the most common causes of allograft loss in kidney transplant recipients. Although the epidemiology and clinical outcomes of glomerulonephritis recurrence occurring after kidney transplantation are relatively well-described, the natural course and optimal treatment strategies of recurrent disease in kidney allografts remain poorly defined. With a greater understanding of the pathophysiology and treatment responses of patients with glomerulonephritis affecting the native kidneys, these discoveries have laid the framework for the potential to improve the management of patients with high-risk glomerulonephritis subtypes being considered for kidney transplantation. SUMMARY Advances in the understanding of the underlying immunopathogenesis of primary GN has the potential to offer novel therapeutic options for kidney patients who develop recurrent disease after kidney transplantation. To test the efficacy of novel treatment options in adequately powered clinical trials requires a more detailed understanding of the clinical and histological characteristics of kidney transplant recipients with recurrent glomerulonephritis.
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Affiliation(s)
- Laura De Souza
- Department of Renal Medicine, Cairns Hospital, Cairns North, Queensland
| | - Janelle Prunster
- Department of Renal Medicine, Cairns Hospital, Cairns North, Queensland
| | - Doris Chan
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth
| | - Aron Chakera
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth
| | - Wai H Lim
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth
- Medical School, University of Western Australia, Crawley, Western Australia, Australia
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24
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Yazılıtaş F, Kargın Çakıcı E, Kurt Şükür ED, Can G, Güngör T, Orhan D, Bülbül M. C3 glomerulopathy: experience of a pediatric nephrology center. Acta Clin Belg 2021; 76:253-257. [PMID: 31914901 DOI: 10.1080/17843286.2020.1713450] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Background: C3 glomerulopathy (C3G) is an uncommon disease characterized by the deposition of complement factors in the glomeruli due to overactivation and dysregulation of the alternative pathway of complement.Objectives: This study aimed to describe the clinicopathological features, laboratory testing, clinical course, treatment, and outcomes of pediatric patients with C3G.Patients and Methods: We reviewed retrospectively the laboratory testing, kidney biopsy reports, and clinical features of 18 patients at our hospital from 2007 to 2019.Results: There were 18 cases, and the majority of the patients were girls (61.1%). The mean age at diagnosis was 11.3 ± 3.7 (5-17) years, and nephritic-nephrotic syndrome presentation in patients was more common (11 cases, 61.1%). Hematuria was found in 66.7% of the patients, of which the majority had microscopic hematuria (58.3%). Hypertension was observed in 10 (55.6%) patients. The mean glomerular filtration rate (eGFR) was 95.7 ± 47.3 mL/min/1.73 m2, and 24-h urinary protein excretion was 76.2 ± 48.6 mg/m2/h. Sixteen patients (88.9%) received renin-angiotensin-aldosterone system blockers (RASB), and two of them were taking RASB only. The majority of patients (83.3%) were treated with immunosuppressive therapy. Eculizumab was also given to one of them. At the last follow-up, two patients had levels of less than 60 mL/min/1.73 m2 for eGFR. Seven patients with immunosuppressive treatment achieved complete remission.Conclusion: C3G shows a variable clinical presentation and response to immunosuppressive therapy. In the present study, we observed that the most common presentation was nephritic and/or nephrotic syndrome and partially responded to treatment to RASB and immunosuppressants.
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Affiliation(s)
- Fatma Yazılıtaş
- Department of Pediatric Nephrology, Ankara Dr.Sami Ulus Maternity and Children Hospital, Ankara, Turkey
| | - Evrim Kargın Çakıcı
- Department of Pediatric Nephrology, Ankara Dr.Sami Ulus Maternity and Children Hospital, Ankara, Turkey
| | - Eda Didem Kurt Şükür
- Department of Pediatric Nephrology, Ankara Dr.Sami Ulus Maternity and Children Hospital, Ankara, Turkey
| | - Gökçe Can
- Department of Pediatric Nephrology, Ankara Dr.Sami Ulus Maternity and Children Hospital, Ankara, Turkey
| | - Tülin Güngör
- Department of Pediatric Nephrology, Ankara Dr.Sami Ulus Maternity and Children Hospital, Ankara, Turkey
| | - Diclehan Orhan
- Department of Pediatric Pathology, Hacettepe University School of Medicine, Ankara, Turkey
| | - Mehmet Bülbül
- Department of Pediatric Nephrology, Ankara Dr.Sami Ulus Maternity and Children Hospital, Ankara, Turkey
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25
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Song H, Zhang M, Li X, Xu F, Zhang D, Zhu X, Zhang J, Qin W, Shi S, Wen J. Generation and Characterization of Mouse Models of C3 Glomerulonephritis With CFI D288G and P467S Mutations. Front Physiol 2021; 12:649801. [PMID: 34149444 PMCID: PMC8209374 DOI: 10.3389/fphys.2021.649801] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 04/07/2021] [Indexed: 11/13/2022] Open
Abstract
C3 glomerulopathy (C3GP) is a disease entity caused by abnormality of the complement alternative pathway (AP) and characterized by C3 deposition in glomeruli. Many variations or mutations of complement factors are believed to underlie the susceptibility to C3GP, but there is a lack of experimental evidence. We have recently reported a patient with C3 glomerulonephritis (C3GN) and compound heterozygosity of two novel variations in the complement factor (CFI). Here, we generated a mouse model to mimic the CFI variations for studying pathogenicity of CFI variations in C3GN development. We used the CRISPR/Cas9 system to make mutant mouse lines that carried D288G and P467S mutations in CFI, respectively, and crossed them to generate mice with compound heterozygosity of CFI D288G and P467S. The mice were all normal in either SPF (specific pathogen free) or regular environment. When treated with lipopolysaccharides (LPS), a bacterial endotoxin that mimics infection and sepsis, the mice developed albuminuria, kidney function impairment, and C3 glomerular deposition at levels comparable with the wild-type mice. The mice with other genotypes concerning CFI D288G and P467S were also tested in parallel. Unexpectedly, we found that the D288G homozygotes all developed severe mesangial deposition of C3 in the LPS model, indicating that CFI D288G variation was involved in the C3 deposition, a key feature of C3GN. The mouse lines generated in the present study can be used to further study the role of CFI variations in C3GN development; in addition, they may be used to screen and test infections and environmental factors capable of triggering C3GN.
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Affiliation(s)
- Hui Song
- National Clinical Research Center for Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Mingchao Zhang
- National Clinical Research Center for Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xue Li
- National Clinical Research Center for Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Feng Xu
- National Clinical Research Center for Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Difei Zhang
- Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Xiaodong Zhu
- National Clinical Research Center for Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jiong Zhang
- National Clinical Research Center for Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Weisong Qin
- National Clinical Research Center for Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Shaolin Shi
- National Clinical Research Center for Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jiqiu Wen
- National Clinical Research Center for Kidney Diseases, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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26
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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: 31] [Impact Index Per Article: 7.8] [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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27
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Demirs JT, Yang J, Crowley MA, Twarog M, Delgado O, Qiu Y, Poor S, Rice DS, Dryja TP, Anderson K, Liao SM. Differential and Altered Spatial Distribution of Complement Expression in Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 2021; 62:26. [PMID: 34160562 PMCID: PMC8237111 DOI: 10.1167/iovs.62.7.26] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 05/19/2021] [Indexed: 12/02/2022] Open
Abstract
Purpose Dysregulation of the alternative complement pathway is a major pathogenic mechanism in age-related macular degeneration. We investigated whether locally synthesized complement components contribute to AMD by profiling complement expression in postmortem eyes with and without AMD. Methods AMD severity grade 1 to 4 was determined by analysis of postmortem acquired fundus images and hematoxylin and eosin stained histological sections. TaqMan (donor eyes n = 39) and RNAscope/in situ hybridization (n = 10) were performed to detect complement mRNA. Meso scale discovery assay and Western blot (n = 31) were used to measure complement protein levels. Results The levels of complement mRNA and protein expression were approximately 15- to 100-fold (P < 0.0001-0.001) higher in macular retinal pigment epithelium (RPE)/choroid tissue than in neural retina, regardless of AMD grade status. Complement mRNA and protein levels were modestly elevated in vitreous and the macular neural retina in eyes with geographic atrophy (GA), but not in eyes with early or intermediate AMD, compared to normal eyes. Alternative and classical pathway complement mRNAs (C3, CFB, CFH, CFI, C1QA) identified by RNAscope were conspicuous in areas of atrophy; in those areas C3 mRNA was observed in a subset of IBA1+ microglia or macrophages. Conclusions We verified that RPE/choroid contains most ocular complement; thus RPE/choroid rather than the neural retina or vitreous is likely to be the key site for complement inhibition to treat GA or earlier stage of the disease. Outer retinal local production of complement mRNAs along with evidence of increased complement activation is a feature of GA.
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Affiliation(s)
- John T. Demirs
- Department of Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States
| | - Junzheng Yang
- Department of Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States
| | - Maura A. Crowley
- Department of Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States
| | - Michael Twarog
- Department of Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States
| | - Omar Delgado
- Department of Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States
| | - Yubin Qiu
- Department of Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States
| | - Stephen Poor
- Department of Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States
| | - Dennis S. Rice
- Department of Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States
| | | | | | - Sha-Mei Liao
- Department of Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, United States
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28
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Pınarbaşı AS, Dursun I, Gokce I, Çomak E, Saygılı S, Bayram MT, Donmez O, Melek E, Tekcan D, Çiçek N, Yılmaz D, Tabel Y, Yıldırım ZY, Bahat E, Koyun M, Soylu A, Canpolat N, Aksu B, Çelakıl ME, Taşdemir M, Benzer M, Özçelik G, Bakkaloğlu SA, Düşünsel R. Predictors of poor kidney outcome in children with C3 glomerulopathy. Pediatr Nephrol 2021; 36:1195-1205. [PMID: 33130981 DOI: 10.1007/s00467-020-04799-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/13/2020] [Accepted: 09/24/2020] [Indexed: 01/22/2023]
Abstract
BACKGROUND C3 glomerulopathy (C3G) is characterized by heterogeneous clinical presentation, outcome, and predominant C3 accumulation in glomeruli without significant IgG. There is scarce outcome data regarding childhood C3G. We describe clinical and pathological features, treatment and outcomes, and risk factors for progression to chronic kidney disease stage 5 (CKD5) in the largest pediatric series with biopsy-proven C3G. METHODS Sixty pediatric patients with C3G from 21 referral centers in Turkey were included in this retrospective study. Patients were categorized according to CKD stage at last visit as CKD5 or non-CKD5. Demographic data, clinicopathologic findings, treatment, and outcome data were compared and possible risk factors for CKD5 progression determined using Cox proportional hazards model. RESULTS Mean age at diagnosis was 10.6 ± 3.0 years and follow-up time 48.3 ± 36.3 months. Almost half the patients had gross hematuria and hypertension at diagnosis. Nephritic-nephrotic syndrome was the commonest presenting feature (41.6%) and 1/5 of patients presented with nephrotic syndrome. Membranoproliferative glomerulonephritis was the leading injury pattern, while 40 patients had only C3 staining. Patients with DDD had significantly lower baseline serum albumin compared with C3GN. Eighteen patients received eculizumab. Clinical remission was achieved in 68.3%. At last follow-up, 10 patients (16.6%) developed CKD5: they had lower baseline eGFR and albumin and higher frequency of nephrotic syndrome and dialysis requirement than non-CKD5 patients. Lower serum albumin and eGFR at diagnosis were independent predictors for CKD5 development. CONCLUSIONS Children with C3G who have impaired kidney function and hypoalbuminemia at diagnosis should be carefully monitored for risk of progression to CKD5. Graphical abstract.
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Affiliation(s)
- Ayşe Seda Pınarbaşı
- Department of Pediatric Nephrology, Erciyes University, Faculty of Medicine, Kayseri, Turkey
| | - Ismail Dursun
- Department of Pediatric Nephrology, Erciyes University, Faculty of Medicine, Kayseri, Turkey.
| | - Ibrahim Gokce
- Department of Pediatric Nephrology, Faculty of Medicine, Marmara University, İstanbul, Turkey
| | - Elif Çomak
- Department of Pediatric Nephrology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Seha Saygılı
- Department of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University, İstanbul, Turkey
| | - Meral Torun Bayram
- Department of Pediatric Nephrology, Faculty of Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Osman Donmez
- Department of Pediatric Nephrology, Faculty of Medicine, Uludağ University, Bursa, Turkey
| | - Engin Melek
- Department of Pediatric Nephrology, Faculty of Medicine, Cukurova University, Adana, Turkey
| | - Demet Tekcan
- Department of Pediatric Nephrology, Faculty of Medicine, Ondokuz Mayıs University, Samsun, Turkey
| | - Neslihan Çiçek
- Department of Pediatric Nephrology, Faculty of Medicine, Marmara University, İstanbul, Turkey
| | - Dilek Yılmaz
- Department of Pediatric Nephrology, Faculty of Medicine, Adnan Menderes University, Aydın, Turkey
| | - Yılmaz Tabel
- Department of Pediatric Nephrology, Faculty of Medicine, İnönü University, Malatya, Turkey
| | - Zeynep Y Yıldırım
- Department of Pediatric Nephrology, Istanbul Faculty of Medicine, Istanbul University, İstanbul, Turkey
| | - Elif Bahat
- Department of Pediatric Nephrology, Faculty of Medicine, Karadeniz Teknik University, Trabzon, Turkey
| | - Mustafa Koyun
- Department of Pediatric Nephrology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Alper Soylu
- Department of Pediatric Nephrology, Faculty of Medicine, Dokuz Eylül University, İzmir, Turkey
| | - Nur Canpolat
- Department of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University, İstanbul, Turkey
| | - Bağdagül Aksu
- Department of Pediatric Nephrology, University of Health Sciences, Haseki Education and Research Hospital, İstanbul, Turkey
| | - Mehtap Ezel Çelakıl
- Department of Pediatric Nephrology, Faculty of Medicine, Kocaeli University, İzmit, Kocaeli, Turkey
| | - Mehmet Taşdemir
- Department of Pediatric Nephrology, Faculty of Medicine, Koç University, İstanbul, Turkey
| | - Meryem Benzer
- Department of Pediatric Nephrology, Bakırköy Dr Sadi Konuk Training and Research Hospital, İstanbul, Turkey
| | - Gül Özçelik
- Department of Pediatric Nephrology, University of Health Sciences, Sisli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey
| | - Sevcan A Bakkaloğlu
- Department of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Ruhan Düşünsel
- Department of Pediatric Nephrology, Erciyes University, Faculty of Medicine, Kayseri, Turkey
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29
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Baker LW, Khan M, Cortese C, Aslam N. Fibrillary glomerulonephritis or complement 3 glomerulopathy: a rare case of diffuse necrotising crescentic glomerulonephritis with C3-dominant glomerular deposition and positive DNAJB9. BMJ Case Rep 2021; 14:e239868. [PMID: 33602773 PMCID: PMC7896581 DOI: 10.1136/bcr-2020-239868] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2021] [Indexed: 11/04/2022] Open
Abstract
Fibrillary glomerulonephritis (FGN) and complement 3 glomerulopathy (C3G) are rare forms of glomerulonephritis with distinct aetiologies. Both FGN and C3G can present with nephritic syndrome. FGN is associated with autoimmune disease, dysproteinaemia, malignancy and hepatitis C infection. C3G is caused by the unregulated activation of the alternative complement pathway. We present a rare case of diffuse necrotising crescentic glomerulonephritis with dominant C3 glomerular staining on immunofluorescence-consistent with C3G-but electron microscopy (EM) findings of randomly oriented fibrils with a mean diameter of 14 nm and positive immunohistochemistry for DNAJB9-suggestive of FGN. To the best of our knowledge, this is the first reported case of FGN to show dominant C3 glomerular deposits. This case report reaffirms the utility of EM in the evaluation of nephritic syndrome and highlights the value of DNAJB9-a novel biomarker with a sensitivity and specificity near 100% for FGN.
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Affiliation(s)
- Lyle Wesley Baker
- Division of Nephrology and Hypertension, Mayo Clinic Hospital Jacksonville, Jacksonville, Florida, USA
| | - Mahnoor Khan
- Division of Nephrology and Hypertension, Mayo Clinic Hospital Jacksonville, Jacksonville, Florida, USA
| | - Cherise Cortese
- Department of Pathology, Mayo Clinic Hospital Jacksonville, Jacksonville, Florida, USA
| | - Nabeel Aslam
- Division of Nephrology and Hypertension, Mayo Clinic Hospital Jacksonville, Jacksonville, Florida, USA
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30
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Zarantonello A, Pedersen H, Laursen NS, Andersen GR. Nanobodies Provide Insight into the Molecular Mechanisms of the Complement Cascade and Offer New Therapeutic Strategies. Biomolecules 2021; 11:biom11020298. [PMID: 33671302 PMCID: PMC7922070 DOI: 10.3390/biom11020298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 01/22/2023] Open
Abstract
The complement system is part of the innate immune response, where it provides immediate protection from infectious agents and plays a fundamental role in homeostasis. Complement dysregulation occurs in several diseases, where the tightly regulated proteolytic cascade turns offensive. Prominent examples are atypical hemolytic uremic syndrome, paroxysmal nocturnal hemoglobinuria and Alzheimer’s disease. Therapeutic intervention targeting complement activation may allow treatment of such debilitating diseases. In this review, we describe a panel of complement targeting nanobodies that allow modulation at different steps of the proteolytic cascade, from the activation of the C1 complex in the classical pathway to formation of the C5 convertase in the terminal pathway. Thorough structural and functional characterization has provided a deep mechanistic understanding of the mode of inhibition for each of the nanobodies. These complement specific nanobodies are novel powerful probes for basic research and offer new opportunities for in vivo complement modulation.
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Affiliation(s)
- Alessandra Zarantonello
- Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark; (A.Z.); (H.P.)
| | - Henrik Pedersen
- Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark; (A.Z.); (H.P.)
| | - Nick S. Laursen
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark;
| | - Gregers R. Andersen
- Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark; (A.Z.); (H.P.)
- Correspondence: ; Tel.: +45-30256646
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31
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Pinarbasi AS, Dursun I, Poyrazoglu MH, Akgun H, Bozpolat A, Dusunsel R. Evaluation of the children with C3 glomerulopathy. SAUDI JOURNAL OF KIDNEY DISEASES AND TRANSPLANTATION 2021; 31:79-89. [PMID: 32129200 DOI: 10.4103/1319-2442.279964] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
C3 glomerulopathy (C3G) is a clinical spectrum that presents with a variety of symptoms, ranging from a mild disease with asymptomatic microhematuria and/or proteinuria to severe disease with nephritic or nephrotic syndrome and renal impairment. Herein, we aim to document the clinical and laboratory findings, response to immunosuppressive and supportive treatment and prognosis of the children with C3G. We retrospectively reviewed the medical records of patients diagnosed with membranoproliferative glomerulonephritis (MPGN). Kidney biopsy materials were reexamined for the diagnosis of C3G. The inclusion criteria for C3G are the dominant C3 staining with or without scanty immunoglobulins (Ig) deposition on immuno- fluorescence (IF) and MPGN patterns on light microscope. Twelve of 69 patients with MPGN were included in the study based on the definition criteria of C3G. Ten of them had only C3 staining and the rest of the patients had both C3 staining and a small amount of IgG/M staining on IF microscopy. One patient was on remission with only ACEI. The rest of the patients used immunosuppressive treatment and two of them needed eculizumab therapy. One of them did not respond to the treatment of eculizumab and progressed to end-stage renal failure. C3G is a disease characterized by a heterogeneous clinical presentation and outcome. Because of this broad spectrum of disease, treatment may vary widely. We think that complement-targeting therapy with eculizumab should be an alternative option for refractory cases, especially in the early stage of disease, if they did not respond to immunosuppressive treatment.
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Affiliation(s)
- Ayse Seda Pinarbasi
- Department of Pediatrics, Division of Pediatric Nephrology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Ismail Dursun
- Department of Pediatrics, Division of Pediatric Nephrology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Muammer Hakan Poyrazoglu
- Department of Pediatrics, Division of Pediatric Nephrology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Hulya Akgun
- Department of Pathology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Adil Bozpolat
- Department of Pediatrics, Nevsehir State Hospital, Nevsehir, Turkey
| | - Ruhan Dusunsel
- Department of Pediatrics, Division of Pediatric Nephrology, Erciyes University Faculty of Medicine, Kayseri, Turkey
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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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Ohtani K. Complement-Related Proteins and Their Measurements: The Current Status of Clinical Investigation. Nephron Clin Pract 2020; 144 Suppl 1:7-12. [PMID: 33232963 DOI: 10.1159/000512494] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 10/21/2020] [Indexed: 11/19/2022] Open
Abstract
Complement has been considered to be a factor that protects the host against invading microorganisms during infection. However, in recent years, complement-related protein deficiency has been found to be involved in the onset of various diseases, such as autoimmune and inflammatory diseases. In Japan, C3, C4, and CH50 tests were generally performed only when a complement system examination was necessary and there were not enough examinations for other complement factors. Since the complement system has a very complicated activation pathway, at present, it is not well known which molecule must be measured to understand the pathological condition or pathogenesis in complement-related diseases. Furthermore, since the frequency of complement factor gene alleles also differs depending on race, data from foreign countries cannot be directly applied to Japanese populations. Under these circumstances, the Japanese Association for Complement Research (JACR) has prepared approximately 20 items for complement-related examinations, including the 5 categories of functional analysis, complement factors, complement regulators, activation products, and autoantibodies.
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Affiliation(s)
- Katsuki Ohtani
- Department of Food Science and Human Wellness, Rakuno Gakuen University, Ebetsu, Japan,
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Complement activity is regulated in C3 glomerulopathy by IgG-factor H fusion proteins with and without properdin targeting domains. Kidney Int 2020; 99:396-404. [PMID: 33129896 PMCID: PMC7863913 DOI: 10.1016/j.kint.2020.09.028] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 09/11/2020] [Accepted: 09/17/2020] [Indexed: 11/29/2022]
Abstract
C3 glomerulopathy is characterized by accumulation of complement C3 within glomeruli. Causes include, but are not limited to, abnormalities in factor H, the major negative regulator of the complement alternative pathway. Factor H-deficient (Cfh-/-) mice develop C3 glomerulopathy together with a reduction in plasma C3 levels. Using this model, we assessed the efficacy of two fusion proteins containing the factor H alternative pathway regulatory domains (FH1-5) linked to either a non-targeting mouse immunoglobulin (IgG-FH1-5) or to an anti-mouse properdin antibody (Anti-P-FH1-5). Both proteins increased plasma C3 and reduced glomerular C3 deposition to an equivalent extent, suggesting that properdin-targeting was not required for FH1-5 to alter C3 activation in either plasma or glomeruli. Following IgG-FH1-5 administration, plasma C3 levels temporally correlated with changes in factor B levels whereas plasma C5 levels correlated with changes in plasma properdin levels. Notably, the increases in plasma C5 and properdin levels persisted for longer than the increases in C3 and factor B. In Cfh-/- mice IgG-FH1-5 reduced kidney injury during accelerated serum nephrotoxic nephritis. Thus, our data demonstrate that IgG-FH1-5 restored circulating alternative pathway activity and reduced glomerular C3 deposition in Cfh-/- mice and that plasma properdin levels are a sensitive marker of C5 convertase activity in factor H deficiency. The immunoglobulin conjugated FH1-5 protein, through its comparatively long plasma half-life, may be a potential therapy for C3 glomerulopathy.
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The Immunopathology of Complement Proteins and Innate Immunity in Autoimmune Disease. Clin Rev Allergy Immunol 2020; 58:229-251. [PMID: 31834594 DOI: 10.1007/s12016-019-08774-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The complement is a powerful cascade of the innate immunity and also acts as a bridge between innate and acquired immune defence. Complement activation can occur via three distinct pathways, the classical, alternative and lectin pathways, each resulting in the common terminal pathway. Complement activation results in the release of a range of biologically active molecules that significantly contribute to immune surveillance and tissue homeostasis. Several soluble and membrane-bound regulatory proteins restrict complement activation in order to prevent complement-mediated autologous damage, consumption and exacerbated inflammation. The crucial role of complement in the host homeostasis is illustrated by association of both complement deficiency and overactivation with severe and life-threatening diseases. Autoantibodies targeting complement components have been described to alter expression and/or function of target protein resulting in a dysregulation of the delicate equilibrium between activation and inhibition of complement. The spectrum of diseases associated with complement autoantibodies depends on which complement protein and activation pathway are targeted, ranging from autoimmune disorders to kidney and vascular diseases. Nevertheless, these autoantibodies have been identified as differential biomarkers for diagnosis or follow-up of disease only in a small number of clinical conditions. For some autoantibodies, a clear relationship with clinical manifestations has been identified, such as anti-C1q, anti-Factor H, anti-C1 Inhibitor antibodies and C3 nephritic factor. For other autoantibodies, the origin and the functional consequences still remain to be elucidated, questioning about the pathophysiological significance of these autoantibodies, such as anti-mannose binding lectin, anti-Factor I, anti-Factor B and anti-C3b antibodies. The detection of autoantibodies targeting complement components is performed in specialized laboratories; however, there is no consensus on detection methods and standardization of the assays is a real challenge. This review summarizes the current panorama of autoantibodies targeting complement recognition proteins of the classical and lectin pathways, associated proteases, convertases, regulators and terminal components, with an emphasis on autoantibodies clearly involved in clinical conditions.
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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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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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Soyaltın E, Çamlar SA, Alaygut D, Mutlubaş F, Yavaşcan Ö, Solakoğlu S, Demir BK. A diagnostic dilemma in a child with macroscopic hematuria, nephrotic syndrome and hypocomplementemia: Answers. Pediatr Nephrol 2020; 35:1213-1216. [PMID: 31950244 DOI: 10.1007/s00467-019-04455-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 11/25/2019] [Accepted: 12/09/2019] [Indexed: 11/24/2022]
Affiliation(s)
- Eren Soyaltın
- Department of Pediatrics, Division of Nephrology, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Seçil Arslansoyu Çamlar
- Department of Pediatrics, Division of Nephrology, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Demet Alaygut
- Department of Pediatrics, Division of Nephrology, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Fatma Mutlubaş
- Department of Pediatrics, Division of Nephrology, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Önder Yavaşcan
- Department of Pediatrics, Division of Nephrology, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey
| | - Seyhun Solakoğlu
- Department of Histology and Embryology, Istanbul University Medical Faculty, Istanbul, Turkey
| | - Belde Kasap Demir
- Department of Pediatrics, Division of Nephrology, University of Health Sciences, Tepecik Training and Research Hospital, Izmir, Turkey. .,Department of Pediatrics, Division of Nephrology and Rheumatology, Izmir Katip Çelebi University Medical Faculty, Izmir, Turkey.
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Hanna RM, Hou J, Hasnain H, Arman F, Selamet U, Wilson J, Olanrewaju S, Zuckerman JE, Barsoum M, Yabu JM, Kurtz I. Diverse Clinical Presentations of C3 Dominant Glomerulonephritis. Front Med (Lausanne) 2020; 7:293. [PMID: 32695788 PMCID: PMC7338606 DOI: 10.3389/fmed.2020.00293] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 05/22/2020] [Indexed: 12/23/2022] Open
Abstract
C3 dominant immunofluorescence staining is present in a subset of patients with idiopathic immune complex membranoproliferative glomerulonephritis (iMPGN). It is increasingly recognized that iMPGN may be complement driven, as are cases of "typical" C3 glomerulopathy (C3G). In both iMPGN and C3G, a frequent membranoproliferative pattern of glomerular injury may indicate common pathogenic mechanisms via complement activation and endothelial cell damage. Dysregulation of the alternative complement pathway and mutations in certain regulatory factors are highly implicated in C3 glomerulopathy (which encompasses C3 glomerulonephritis, dense deposit disease, and cases of C3 dominant MPGN). We report three cases that demonstrate that an initial biopsy diagnosis of iMPGN does not exclude complement alterations similar to the ones observed in patients with a diagnosis of C3G. The first patient is a 39-year-old woman with iMPGN and C3 dominant staining, with persistently low C3 levels throughout her course. The second case is a 22-year-old woman with elevated anti-factor H antibodies and C3 dominant iMPGN findings on biopsy. The third case is a 25-year-old woman with C3 dominant iMPGN, dense deposit disease, and a crescentic glomerulonephritis on biopsy. We present the varied phenotypic variations of C3 dominant MPGN and review clinical course, complement profiles, genetic testing, treatment course, and peri-transplantation plans. Testing for complement involvement in iMPGN is important given emerging treatment options and transplant planning.
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Affiliation(s)
- Ramy M Hanna
- Division of Nephrology, Department of Medicine, UCI School of Medicine, Irvine, CA, United States.,Department of Medicine, Division of Nephrology, David Geffen UCLA School of Medicine, Los Angeles, CA, United States
| | - Jean Hou
- Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, CA, United States
| | - Huma Hasnain
- Department of Medicine, Division of Nephrology, David Geffen UCLA School of Medicine, Los Angeles, CA, United States
| | - Farid Arman
- Department of Medicine, Division of Nephrology, David Geffen UCLA School of Medicine, Los Angeles, CA, United States
| | - Umut Selamet
- Department of Medicine, Division of Nephrology, David Geffen UCLA School of Medicine, Los Angeles, CA, United States.,Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, United States
| | - James Wilson
- Department of Medicine, Division of Nephrology, David Geffen UCLA School of Medicine, Los Angeles, CA, United States
| | - Samuel Olanrewaju
- David Geffen UCLA School of Medicine, Los Angeles, CA, United States
| | - Jonathan E Zuckerman
- Department of Pathology and Laboratory Medicine, David Geffen UCLA School of Medicine, Los Angeles, CA, United States
| | - Marina Barsoum
- Department of Medicine, Division of Nephrology, David Geffen UCLA School of Medicine, Los Angeles, CA, United States
| | - Julie M Yabu
- Department of Medicine, Division of Nephrology, David Geffen UCLA School of Medicine, Los Angeles, CA, United States
| | - Ira Kurtz
- Department of Medicine, Division of Nephrology, David Geffen UCLA School of Medicine, Los Angeles, CA, United States.,UCLA Brain Research Institute, Los Angeles, CA, United States
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Lundquist AL, Kalim S, Mojtahed A, Tomaszewski KJ. Case 13-2020: A 29-Year-Old Man with High Blood Pressure, Renal Insufficiency, and Hematuria. N Engl J Med 2020; 382:1639-1647. [PMID: 32320573 DOI: 10.1056/nejmcpc1916254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- Andrew L Lundquist
- From the Departments of Medicine (A.L.L., S.K.), Radiology (A.M.), and Pathology (K.J.T.), Massachusetts General Hospital, and the Departments of Medicine (A.L.L., S.K.), Radiology (A.M.), and Pathology (K.J.T.), Harvard Medical School - both in Boston
| | - Sahir Kalim
- From the Departments of Medicine (A.L.L., S.K.), Radiology (A.M.), and Pathology (K.J.T.), Massachusetts General Hospital, and the Departments of Medicine (A.L.L., S.K.), Radiology (A.M.), and Pathology (K.J.T.), Harvard Medical School - both in Boston
| | - Amirkasra Mojtahed
- From the Departments of Medicine (A.L.L., S.K.), Radiology (A.M.), and Pathology (K.J.T.), Massachusetts General Hospital, and the Departments of Medicine (A.L.L., S.K.), Radiology (A.M.), and Pathology (K.J.T.), Harvard Medical School - both in Boston
| | - Kristen J Tomaszewski
- From the Departments of Medicine (A.L.L., S.K.), Radiology (A.M.), and Pathology (K.J.T.), Massachusetts General Hospital, and the Departments of Medicine (A.L.L., S.K.), Radiology (A.M.), and Pathology (K.J.T.), Harvard Medical School - both in Boston
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Wani AS, Zahir Z, Gupta A, Agrawal V. Clinicopathological Significance and Renal Outcomes of Light Microscopic Patterns in Complement Component 3 Glomerulopathy. Nephron Clin Pract 2020; 144:228-235. [PMID: 32155638 DOI: 10.1159/000506290] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 01/30/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Complement component 3 glomerulopathy (C3G) is a disease diagnosed based on the predominance of C3 immunostaining in glomeruli. The popular electron microscopic subtyping of C3G into dense deposit disease and C3 glomerulonephritis (GN) is not without limitations. We aimed to study the light microscopic (LM) patterns of C3G along with their clinicopathological correlation and treatment outcome. METHODS C3G biopsies were classified into 4 LM patterns (membranoproliferative GN [MPGN], mesangial proliferative GN [MesPGN], diffuse proliferative GN [DPGN], and crescentic GN [CrGN]). These patterns were compared for clinicopathological profile, treatment outcome, and renal survival. Further, predictors of end-stage renal disease (ESRD) were determined using the Cox proportional hazards model. RESULTS Of 162 biopsies, there were 83 MPGN, 36 DPGN, 22 MesPGN, and 21 CrGN. Majority of the patients were young, with males being more than females. About half (48%) of the patients received immunosuppression, steroids alone (29%) or steroids with other immunosuppressants (19%). The overall remission rate was 32.7% (median follow-up = 14 months). CKD developed in 46 patients and 31 patients progressed to ESRD. Predictors of progression to ESRD were older age (hazard ratio [HR] = 1.04, p < 0.01), advanced renal failure at presentation (HR = 3.73, p < 0.01), glomerulosclerosis (HR = 5.07, p < 0.01), and severity of interstitial fibrosis and tubular atrophy (HR = 8.25, p = 0.01). CONCLUSIONS The LM patterns differed in their clinicopathological profiles, without any significant difference in their renal outcomes. Glomerulosclerosis and interstitial fibrosis portend a poor prognosis. Besides CrGN, MesPGN pattern of C3G presented as a severe form of disease.
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Affiliation(s)
- Asif Sadiq Wani
- Department of Nephrology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Zafirah Zahir
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India,
| | - Amit Gupta
- Department of Nephrology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Vinita Agrawal
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Snijders MLH, van de Wall-Neecke BJ, Hesselink DA, Becker JU, Clahsen-van Groningen MC. Utility of immunohistochemistry with C3d in C3 glomerulopathy. Mod Pathol 2020; 33:431-439. [PMID: 31477814 DOI: 10.1038/s41379-019-0348-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 07/30/2019] [Accepted: 07/30/2019] [Indexed: 01/13/2023]
Abstract
C3-dominance by immunofluorescence is a defining feature in the diagnosis of C3 glomerulopathy. Most pathologists stain for C3c, which has been reported as a trace/negative even in otherwise clear-cut cases of dense deposit disease. We investigated the usefulness of C3d immunohistochemistry in biopsies with C3 glomerulopathy as an ancillary diagnostic tool. All biopsies from patients diagnosed with C3 glomerulopathy in the period January 2005 to June 2017 in the Erasmus MC, Rotterdam were included (n = 14; 10 C3 glomerulonephritis, 4 dense deposit disease). The staining pattern of C3d and C4d by immunohistochemistry was analyzed. As controls, biopsies from patients with immune complex membranoproliferative glomerulonephritis (n = 2), infection-associated glomerulonephritis (n = 6), pauci-immune crescentic glomerulonephritis (n = 7), tubulointerstitial nephritis (n = 7) and chronic-active antibody-mediated rejection (n = 9) were included. All 14 biopsies with C3 glomerulopathy showed a C3d score of ≥2, including two clear-cut biopsies with C3 glomerulopathy originally showing a trace/negative staining for C3c. In the control group, a C3d score ≥2 was observed in 11 biopsies (35%; 2 with immune complex membranoproliferative glomerulonephritis (100%), 6 with infection-associated glomerulonephritis (100%), 1 with pauci-immune crescentic glomerulonephritis (14%), 1 with tubulointerstitial nephritis (14%) and 1 with chronic-active antibody-mediated rejection (11%)). C4d was positive in 71% of the biopsies with C3 glomerulopathy (10/14). In conclusion, C3d immunohistochemistry is a valuable tool in the diagnosis of C3 glomerulopathy, especially in cases in which C3c immunofluorescence shows a trace/negative. We recommend the use of C3d in addition to C3c in cases suspicious for C3 glomerulopathy.
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Affiliation(s)
- Malou L H Snijders
- Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
| | | | - Dennis A Hesselink
- Department of Internal Medicine, Division of Nephrology and Renal Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Jan U Becker
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
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Chamarthi G, Clapp WL, Bejjanki H, Auerbach J, Koratala A. Infection-related Glomerulonephritis and C3 Glomerulonephritis - Similar Yet Dissimilar: A Case Report and Brief Review of Current Literature. Cureus 2020; 12:e7127. [PMID: 32140372 PMCID: PMC7047932 DOI: 10.7759/cureus.7127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Infection-related glomerulonephritis (IRGN) is an immune complex-mediated glomerulonephritis (GN), often preceded by infection with subsequent recovery of renal function after the resolution of the infection. C3 deposition in the absence of immune complex deposits can be seen in patients with IRGN, but with the emergence of C3 glomerulonephritis (C3GN), the distinction is difficult as the clinical and pathological presentation may be similar. However, their treatment and clinical course vary significantly. A 64-year-old man with a history of hypertension and bioprosthetic aortic valve presented to the Emergency Department with left upper quadrant (LUQ) pain and a purpuric rash on bilateral lower extremities. The patient became septic, and further workup during the hospitalization revealed endocarditis secondary to Streptococcus viridans. On admission, the patient had acute kidney injury (AKI) with a serum creatinine of 3.79 mg/dl, which peaked at 5.72 mg/dl during the hospitalization. Renal biopsy demonstrated segmental necrotizing glomerulonephritis on light microscopy, predominant C3 deposition on immunofluorescence (IF) staining, and mesangial and paramesangial deposits on electron microscopy. This histologic picture can be seen both in IRGN and C3GN. The patient was treated with intravenous ceftriaxone for six weeks for endocarditis and the kidney injury was managed with supportive care. The patient’s renal function improved and complement levels normalized, supporting the diagnosis of IRGN retrospectively. IRGN can mimic C3GN, and evaluation for alternate pathways of the complement system may be warranted in patients with atypical presentation of IRGN.
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Affiliation(s)
| | | | | | - Jena Auerbach
- Pathology, University of Florida Health, Gainesville, USA
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Sethi S, Fervenza FC. Standardized classification and reporting of glomerulonephritis. Nephrol Dial Transplant 2020; 34:193-199. [PMID: 30124958 DOI: 10.1093/ndt/gfy220] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Accepted: 06/07/2018] [Indexed: 11/13/2022] Open
Abstract
A kidney biopsy is done to determine the etiology of the glomerulonephritis (GN) and the severity of the lesion, to identify whether other lesions, related to or not related to the GN, are present on the kidney biopsy and finally to ascertain the extent of chronicity of the GN. The etiology of GN is based on the classification of GN into five groups: immune complex-mediated GN, antineutrophil cytoplasmic antibody (ANCA)-associated GN, anti-glomerular basement membrane (GBM) GN, monoclonal immunoglobulin-mediated GN and C3 glomerulopathy. Immune complex GN includes multiple specific diseases such as lupus nephritis, IgA nephropathy, infection-related GN and fibrillary GN. ANCA GN, anti-GBM GN and C3 glomerulopathy are specific diseases in themselves, while monoclonal Ig GN includes proliferative GN with monoclonal Ig deposits and monoclonal Ig deposition disease. Thus identification of the class of GN and within it the specific disease determines the etiology of GN. Ancillary studies may be required to confirm the etiology of GN. The severity of the GN is revealed by the pattern of injury, such as crescentic, necrotizing, diffuse proliferative, exudative, membranoproliferative, mesangial proliferative or a sclerosing GN. Secondary diagnosis either related or unrelated to the GN, such as diabetic glomerulosclerosis, acute tubular necrosis or thrombotic microangiopathy, may also be present. The secondary diagnosis may sometimes be the reason for the kidney biopsy. The chronicity of GN is determined by evaluating the extent of glomerulosclerosis, tubular atrophy and interstitial fibrosis and vascular sclerosis present on the biopsy. This review summarizes the approach to standardizing a kidney biopsy report that includes these components in a logical and sequential manner.
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Affiliation(s)
- Sanjeev Sethi
- Department of Internal Medicine, Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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Schena FP, Esposito P, Rossini M. A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease. Int J Mol Sci 2020; 21:E525. [PMID: 31947692 PMCID: PMC7013756 DOI: 10.3390/ijms21020525] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/09/2020] [Accepted: 01/10/2020] [Indexed: 02/07/2023] Open
Abstract
In April 2012, a group of nephrologists organized a consensus conference in Cambridge (UK) on type II membranoproliferative glomerulonephritis and decided to use a new terminology, "C3 glomerulopathy" (C3 GP). Further knowledge on the complement system and on kidney biopsy contributed toward distinguishing this disease into three subgroups: dense deposit disease (DDD), C3 glomerulonephritis (C3 GN), and the CFHR5 nephropathy. The persistent presence of microhematuria with or without light or heavy proteinuria after an infection episode suggests the potential onset of C3 GP. These nephritides are characterized by abnormal activation of the complement alternative pathway, abnormal deposition of C3 in the glomeruli, and progression of renal damage to end-stage kidney disease. The diagnosis is based on studying the complement system, relative genetics, and kidney biopsies. The treatment gap derives from the absence of a robust understanding of their natural outcome. Therefore, a specific treatment for the different types of C3 GP has not been established. Recommendations have been obtained from case series and observational studies because no randomized clinical trials have been conducted. Current treatment is based on corticosteroids and antiproliferative drugs (cyclophosphamide, mycophenolate mofetil), monoclonal antibodies (rituximab) or complement inhibitors (eculizumab). In some cases, it is suggested to include sessions of plasma exchange.
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Affiliation(s)
- Francesco Paolo Schena
- Department of Emergency and Organ Transplantation, Renal Unit, University of Bari, 70124 Bari, Italy;
- Schena Foundation, European Center for the Study of Renal Diseases, 70010 Valenzano, Italy
| | - Pasquale Esposito
- Department of Internal Medicine, Division of Nephrology, Dialysis and Transplantation, University of Genoa and IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy;
| | - Michele Rossini
- Department of Emergency and Organ Transplantation, Renal Unit, University of Bari, 70124 Bari, Italy;
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Feng J, Yu J, Wang X, Wang Y, Liu Y, Xu Z, Sun W. Concurrent anti-neutrophil cytoplasmic antibody-associated glomerulonephritis and IgG4-associated tubulointerstitial nephritis with C3 glomerulonephritis: A case report. Medicine (Baltimore) 2020; 99:e18857. [PMID: 32000387 PMCID: PMC7004583 DOI: 10.1097/md.0000000000018857] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
RATIONALE IgG4-related disease (IgG4-RD) is a slowly progressing inflammatory disease that can involve multiple organ systems. There is considerable overlap between IgG4-RDs and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Herein, we present an unusual case of IgG4-associated tubulointerstitial nephritis (IgG4-TIN) and ANCA-associated glomerulonephritis (ANCA-GN) co-occurring with C3 glomerulonephritis (C3GN). PATIENT CONCERNS A 72-year-old male was admitted to hospital because of fever and fatigue. He was diagnosed with elevated serum creatinine and IgG4 levels, and was positive for ANCA. DIAGNOSIS Initially, the pathology supported a diagnosis of IgG4-TIN and ANCA-GN; however, further examination revealed he also had C3GN. INTERVENTIONS The patient was treated with methylprednisolone and cyclophosphamide and received regular follow-up care. OUTCOMES After treatment, the patient no longer exhibited fever or fatigue and had no complications. The seven-month follow-up showed downward trends in IgG4 and MPO-ANCA levels and stable 24-hour urine protein, serum creatinine levels. LESSONS Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis and IgG4-associated tubulointerstitial nephritis with C3glomerulonephritis rarely occur simultaneously. Laboratory analysis and pathology are both needed to ensure diagnostic accuracy. However, in this case, the three diseases overlapped to such a large extent that achieving a definitive diagnosis was particularly challenging. Timely and accurate diagnosis is crucial for selecting the best treatment course and optimizing patient outcome.
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Affiliation(s)
| | | | - Xueyao Wang
- Department of Ultrasound, The First Hospital of Jilin University, Changchun, Jilin, China
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Monoclonal immunoglobulin mediates complement activation in monoclonal gammopathy associated-C3 glomerulonephritis. BMC Nephrol 2019; 20:459. [PMID: 31823738 PMCID: PMC6902416 DOI: 10.1186/s12882-019-1640-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 11/22/2019] [Indexed: 12/28/2022] Open
Abstract
Background C3 glomerulonephritis (C3GN) is a rare disease caused by inherited or acquired complement alternative pathway (CAP) dysregulation, which could also be secondary to monoclonal gammopathy of undetermined significance (MGUS). Herein, we described a patient presenting with C3GN and monoclonal gammopathy, and the pathogenic association between the two diseases was further explored in vitro. Case presentation A 76-year-old Chinese man presented with low serum C3 level, haematuria and nephrotic syndrome, and experienced rapid worsening of renal function over a period of 10 months. His serum and urine immunofixation electrophoresis both revealed a monoclonal IgGλ. A bone marrow puncture showed plasma cell dyscrasias with the highest plasma cell count of 5.25%. Kidney biopsy showed the presence of C3 glomerulonephritis, with exclusive deposits of C3 visible on immunofluorescence, a membranoproliferative pattern on light microscopy and electron dense deposits in sub-epithelial, intramembranous, sub-endothelial and mesangial regions by electron microscopy. The patient was positive for C3 nephritic factor (C3NeF) activity and anti-CFH autoantibodies, and all became negative during disease remission. The anti-CFH autoantibodies purified from the patient’s plasma exchange fluids were proven to be a monoclonal IgGλ, and could inhibit CFH binding to C3b and accelerate the formation of C3 convertase indirectly by interfering with the formation-impeding activity of CFH. No deficiency of candidate genes, especially variants in CFH, was detected in our patient. Based on the pathological and laboratory findings, the diagnosis of monoclonal gammopathy of renal significance (MGRS)-associated C3GN was finally made. Conclusions This is the first demonstration that intact monoclonal immunoglobulin (IgGλ) could act as an anti-CFH antibody and lead to MGRS-associated C3GN by activating the CAP.
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Abstract
Glomerulonephritis (GN) refers to a group of renal diseases affecting the glomeruli due to the damage mediated by immunological mechanisms. A large proportion of the disease manifestations are caused by disturbances in the complement system. They can be due to genetic errors, autoimmunity, microbes or abnormal immunoglobulins, like modified IgA or paraproteins. The common denominator in most of the problems is an overactive or misdirected alternative pathway complement activation. An assessment of kidney function, amount of proteinuria and hematuria are crucial elements to evaluate, when glomerulonephritis is suspected. However, the cornerstones of the diagnoses are renal biopsy and careful examination of the complement abnormality. Differential diagnostics between the various forms of GN is not possible based on clinical features, as they may vary greatly. This review describes the known mechanisms of complement dysfunction leading to different forms of primary GN (like IgA glomerulonephritis, dense deposit disease, C3 glomerulonephritis, post-infectious GN, membranous GN) and differences to atypical hemolytic uremic syndrome. It also covers the basic elements of etiology-directed therapy and prognosis of the most common forms of GN. Common principles in the management of GN include treatment of hypertension and reduction of proteinuria, some require immunomodulating treatment. Complement inhibition is an emerging treatment option. A thorough understanding of the basic disease mechanism and a careful follow-up are needed for optimal therapy.
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Affiliation(s)
- Kati Kaartinen
- Department of Nephrology, Abdominal Center, Helsinki University Central Hospital, Helsinki, Finland
| | - Adrian Safa
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Soumya Kotha
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Giorgio Ratti
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland
| | - Seppo Meri
- Department of Biomedical Sciences, Humanitas University, Milan, Italy; Department of Bacteriology and Immunology, Translational Immunology Research Program, University of Helsinki, Helsinki, Finland; HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
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Kumar A, Ramachandran R, Rawat A, Das R, Rayat CS, Kenwar DB, Sharma A, Gupta KL, Nada R. Poor allograft outcome in Indian patients with post-transplant C3 glomerulopathy. Clin Kidney J 2019; 14:291-300. [PMID: 33564431 PMCID: PMC7857824 DOI: 10.1093/ckj/sfz135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 09/07/2019] [Indexed: 11/12/2022] Open
Abstract
Background Complement 3 glomerulopathy (C3G) results from dysfunction of the alternative complement pathway (ACP). No data are available on post-transplant C3G in South Asia. Methods In this study, renal allograft biopsies of C3G patients performed from 2012 to 2017 were analysed for ACP functional assay (APFA), serum complement levels, complement factor H (CFH), complement factor B (CFB) and autoantibodies to CFH and CFB. Limited genetic screening for CFH/CFHR5 genes was carried out. All study patients were also followed up. Results A total of 21 cases of C3G were included, of which 11 had native C3G disease (that is, recurrent C3G). Of these 11 recurrent cases, 7 presented with allograft dysfunction and 4 with proteinuria and renal dysfunction. Early post-transplant recurrence (<1 month) was noted in six patients, whereas recurrence in five patients occurred within 8–17 months of transplant. Biopsies showed mild focal mesangial expansion with or without endocapillary proliferation and thrombotic microangiopathy. Rejection was also noted in six patients. APFA/C3 levels were low in all cases. Serum CFH levels were low [dense deposit disease (DDD), 44%; C3 glomerulonephritis (C3GN), 25%], whereas CFB levels were normal. Autoantibodies to CFH, CFB and C3 nephritic factor were present in 11, 0 and 44% of DDD cases, respectively, and in 17, 17 and 33% of C3GN cases, respectively. Genetic analysis revealed only non-pathogenic CFH gene variants (93%). No novel mutation was found. At follow-up (140 months), stable graft was noted in 28% of cases, progressive renal failure in 19%, graft loss in 34%, and 19% of patients died. Conclusion Post-transplant C3G can present with graft dysfunction and/or proteinuria. Subtle histological findings demand careful interpretation of immunofluorescence results. Autoantibodies to complement pathway regulatory proteins are common, and no novel mutation has been found from limited genetic workup. Clinical outcome is poor.
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Affiliation(s)
- Ashwani Kumar
- Department of Histopathology, PGIMER, Chandigarh, India
| | | | - Amit Rawat
- Department of Pediatrics, PGIMER, Chandigarh, India
| | - Reena Das
- Department of Hematology, PGIMER, Chandigarh, India
| | | | | | - Ashish Sharma
- Department of Transplant Surgery, PGIMER, Chandigarh, India
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