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1
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Lin DW, Chang CC, Hsu YC, Lin CL. New Insights into the Treatment of Glomerular Diseases: When Mechanisms Become Vivid. Int J Mol Sci 2022; 23:3525. [PMID: 35408886 PMCID: PMC8998908 DOI: 10.3390/ijms23073525] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/18/2022] [Accepted: 03/22/2022] [Indexed: 12/23/2022] Open
Abstract
Treatment for glomerular diseases has been extrapolated from the experience of other autoimmune disorders while the underlying pathogenic mechanisms were still not well understood. As the classification of glomerular diseases was based on patterns of juries instead of mechanisms, treatments were typically the art of try and error. With the advancement of molecular biology, the role of the immune agent in glomerular diseases is becoming more evident. The four-hit theory based on the discovery of gd-IgA1 gives a more transparent outline of the pathogenesis of IgA nephropathy (IgAN), and dysregulation of Treg plays a crucial role in the pathogenesis of minimal change disease (MCD). An epoch-making breakthrough is the discovery of PLA2R antibodies in the primary membranous nephropathy (pMN). This is the first biomarker applied for precision medicine in kidney disease. Understanding the immune system's role in glomerular diseases allows the use of various immunosuppressants or other novel treatments, such as complement inhibitors, to treat glomerular diseases more reasonable. In this era of advocating personalized medicine, it is inevitable to develop precision medicine with mechanism-based novel biomarkers and novel therapies in kidney disease.
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Affiliation(s)
- Da-Wei Lin
- Department of Internal Medicine, St. Martin De Porres Hospital, Chiayi 60069, Taiwan;
| | - Cheng-Chih Chang
- Department of Surgery, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan;
| | - Yung-Chien Hsu
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
| | - Chun-Liang Lin
- Department of Nephrology, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 613016, Taiwan
- Division of Chinese Materia Medica Development, National Research Institute of Chinese Medicine, Taipei 613016, Taiwan
- Kidney Research Center, Chang Gung Memorial Hospital, Taipei 613016, Taiwan
- Center for Shockwave Medicine and Tissue Engineering, Chang Gung Memorial Hospital, Kaohsiung 833253, Taiwan
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2
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Tamura H. Trends in pediatric nephrotic syndrome. World J Nephrol 2021; 10:88-100. [PMID: 34631479 PMCID: PMC8477269 DOI: 10.5527/wjn.v10.i5.88] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/15/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Nephrotic syndrome (NS) is relatively common in children, with most of its histological types being minimal changed disease. Its etiology has long been attributed to lymphocyte (especially T-cell) dysfunction, while T-cell-mediated vascular hyperpermeability increases protein permeability in glomerular capillaries, leading to proteinuria and hypoproteinemia. Based on this etiology, steroids and immunosuppressive drugs that are effective against this disease have also been considered to correct T-cell dysfunction. However, in recent years, this has been questioned. The primary cause of NS has been considered damage to glomerular epithelial cells and podocyte-related proteins. Therefore, we first describe the changes in expression of molecules involved in NS etiology, and then describe the mechanism by which abnormal expression of these molecules induces proteinuria. Finally, we consider the mechanism by which infection causes the recurrence of NS.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
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3
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Tamura H, Kuraoka S, Hidaka Y, Nagata H, Furuie K, Nakazato H. A Case of Nephrotic Syndrome that Resolved with Influenza B Infection. Case Rep Nephrol Dial 2021; 11:103-109. [PMID: 34055920 PMCID: PMC8138236 DOI: 10.1159/000515062] [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: 10/21/2020] [Accepted: 01/29/2021] [Indexed: 01/24/2023] Open
Abstract
It has been postulated that measles virus infection is associated with remission of idiopathic nephrotic syndrome (INS) in childhood. There are few reports on the correlation of INS remission with other infections. Previously, there have been two case reports suggesting an association between influenza B virus infection and the remission of INS. The patient was an 18-year-old Japanese woman. The onset of steroid-sensitive NS was at 9 years of age, and pathological diagnosis was minimal change nephrotic syndrome (MCNS). Until 10 months prior to visiting our hospital, the patient's NS was in remission. The patient experienced fever, cough, and malaise and she was diagnosed with type B influenza by a local physician 4 days before visiting our hospital. The patient had vomiting and diarrhea 1 day prior to visiting our hospital. Her weight was 54.7 kg (+5.0 kg) and she had pitting edema of both lower legs. Her serum albumin level was 0.9 g/dL, proteinuria level was 8.73 g/gCr, and urine sediments showed 1-4 red blood cells per high-power field. She was diagnosed with relapse of NS. The level of proteinuria decreased to 0.03 g/gCr with rest alone on day 4 of admission, and a complete remission from NS was observed at approximately 2 weeks after the onset of influenza B infection. We report a rare case wherein spontaneous remission of NS occurred within a short period of 2 weeks after influenza B infection. It is clear that some immunity is involved in the pathogenesis of INS, but there are some cases in which infection improves NS and others in which it recurs.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Shohei Kuraoka
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuko Hidaka
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroko Nagata
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Keishiro Furuie
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Hitoshi Nakazato
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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Nishino Y, Enya T, Miyazaki K, Morimoto Y, Marutani S, Okada M, Sugimoto K. The potentially therapeutic role of tonsillectomy in the alleviation of several renal diseases apart from IgA nephropathy. Med Hypotheses 2020; 146:110405. [PMID: 33261919 DOI: 10.1016/j.mehy.2020.110405] [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: 06/09/2020] [Revised: 11/15/2020] [Accepted: 11/17/2020] [Indexed: 11/26/2022]
Abstract
Tonsils are located mainly at the gateway of the respiratory tract, and are reportedly one of the secondary lymphatic organs of the immune system. The development of several diseases including IgA nephropathy (IgAN) is associated with inflammatory stimulation and an aberrant immune response of the tonsils. Several studies have reported an improvement in and/or an increase in the stability of the clinicopathological findings of patients with IgAN post tonsillectomy. However, the efficacy in and precise mechanism of the alleviation of symptoms of other renal diseases by tonsillectomy remain unknown. We hypothesize that tonsillectomy may play a potentially therapeutic role in renal diseases apart from IgAN, which are thought to be caused by an impaired regulation of the immune system.
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Affiliation(s)
- Yuuki Nishino
- Department of Pediatrics, Kindai University, Faculty of Medicine, Osaka, Japan
| | - Takuji Enya
- Department of Pediatrics, Kindai University, Faculty of Medicine, Osaka, Japan
| | - Kohei Miyazaki
- Department of Pediatrics, Kindai University, Faculty of Medicine, Osaka, Japan
| | - Yuichi Morimoto
- Department of Pediatrics, Kindai University, Faculty of Medicine, Osaka, Japan
| | - Satoshi Marutani
- Department of Pediatrics, Kindai University, Faculty of Medicine, Osaka, Japan
| | - Mitsuru Okada
- Department of Pediatrics, Kindai University, Faculty of Medicine, Osaka, Japan
| | - Keisuke Sugimoto
- Department of Pediatrics, Kindai University, Faculty of Medicine, Osaka, Japan.
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5
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Nishikawa M, Shimada N, Kawazoe T, Sawaki R, Ikuta H, Kanzaki M, Fukuoka K, Fukushima M, Asano K. Long-term Successful Treatment of Rituximab for Steroid-resistant Minimal Change Nephrotic Syndrome and Idiopathic Thrombocytopenic Purpura. Intern Med 2020; 59:983-986. [PMID: 31866629 PMCID: PMC7184077 DOI: 10.2169/internalmedicine.3837-19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 11/04/2019] [Indexed: 01/19/2023] Open
Abstract
A 22-year-old woman had been diagnosed with idiopathic thrombocytopenic purpura (ITP) 5 years earlier. After undergoing splenectomy, she relapsed frequently following prednisolone tapering. She was complicated with minimal change nephrotic syndrome (MCNS) while taking 20 mg of prednisolone. Despite treatment with prednisolone, cyclosporin and low-density lipoprotein-apheresis, MCNS and ITP did not improve. We added rituximab in 4 weekly infusions of 375 mg/m2. MCNS and ITP were in complete remission. After administering rituximab once, all medicines were discontinued. No relapse had occurred by 50 months following the first rituximab administration. Rituximab affects steroid-resistant MCNS and ITP for a long time without complications.
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Affiliation(s)
- Mana Nishikawa
- Department of Nephrology, Kurashiki Central Hospital, Japan
| | | | | | - Ryo Sawaki
- Department of Nephrology, Kurashiki Central Hospital, Japan
| | - Haruka Ikuta
- Department of Nephrology, Kurashiki Central Hospital, Japan
| | - Motoko Kanzaki
- Department of Nephrology, Kurashiki Central Hospital, Japan
| | - Kosuke Fukuoka
- Department of Nephrology, Kurashiki Central Hospital, Japan
| | - Masaki Fukushima
- Department of Internal Medicine, Shigei Research Institute Hospital, Japan
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Guimarães FTL, Ferreira RN, Brito-Melo GEA, Rocha-Vieira E, Pereira WDF, Pinheiro SVB, Miranda AS, Simões E Silva AC. Pediatric Patients With Steroid-Sensitive Nephrotic Syndrome Have Higher Expression of T Regulatory Lymphocytes in Comparison to Steroid-Resistant Disease. Front Pediatr 2019; 7:114. [PMID: 31001501 PMCID: PMC6455073 DOI: 10.3389/fped.2019.00114] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 03/08/2019] [Indexed: 12/13/2022] Open
Abstract
Background and Aim: Idiopathic nephrotic syndrome (INS) is classified according to the response to drug therapy in steroid-sensitive (SS), steroid-dependent (SD), and steroid-resistant (SR) categories. Previous studies showed changes in inflammatory activity of subpopulations of lymphocytes in INS. This study aimed to compare SS and SR patients in regard to subpopulations of leukocytes, profile of regulatory lymphocytes, and migratory activity of lymphocyte subpopulations. Results obtained in INS patients were also compared to age and sex-matched healthy controls. Methods: This is a cross-sectional study including SS patients (n = 30), SR patients (n = 14), and controls (n = 10). Peripheral blood samples were withdrawn for ex-vivo leukocyte flow cytometry analysis. Results: Percentage of B-lymphocytes and natural killer (NK) cells were significantly reduced in SR patients when compared to controls, while the percentage of NKT cells were decreased in SS patients in comparison to controls. Percentages of CD4+ expressing FoxP3 and CTLA4 were significantly higher in SS patients in comparison to SR patients and controls. The expression of integrin CD18 on the surface of T lymphocytes (CD3+) was reduced in SS patients if compared to controls. Conclusion: This study found that SS INS patients have higher levels of regulatory T-lymphocytes and lower expression of adhesion molecules than SR patients.
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Affiliation(s)
- Fabio Tadeu Lourenço Guimarães
- Centro Integrado de Pós-Graduação e Pesquisa em Saúde - CIPq, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
| | - Rodrigo Novaes Ferreira
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Gustavo Eustáquio Alvim Brito-Melo
- Centro Integrado de Pós-Graduação e Pesquisa em Saúde - CIPq, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
| | - Etel Rocha-Vieira
- Centro Integrado de Pós-Graduação e Pesquisa em Saúde - CIPq, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
| | - Wagner de Fátima Pereira
- Centro Integrado de Pós-Graduação e Pesquisa em Saúde - CIPq, Universidade Federal dos Vales do Jequitinhonha e Mucuri (UFVJM), Diamantina, Brazil
| | - Sérgio Veloso Brant Pinheiro
- Unidade de Nefrologia Pediátrica, Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Aline Silva Miranda
- Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.,Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Ana Cristina Simões E Silva
- Unidade de Nefrologia Pediátrica, Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.,Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
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Takakura M, Shimizu M, Mizuta M, Inoue N, Tasaki Y, Ohta K, Furuichi K, Wada T, Yachie A. Successful treatment of rituximab- and steroid-resistant nephrotic syndrome with leukocytapheresis. J Clin Apher 2018; 33:409-411. [PMID: 29341230 DOI: 10.1002/jca.21613] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 12/21/2017] [Accepted: 12/23/2017] [Indexed: 11/10/2022]
Abstract
Although rituximab (RTX) is a promising therapeutic agent for treating steroid-resistant nephrotic syndrome (SRNS) resistant to various immunosuppressive agents, some patients have shown resistance to RTX. We report the case of a patient with RTX-resistant nephrotic syndrome and SRNS who was successfully treated with leukocytapheresis (LCAP). After LCAP, there was a significant reduction in proteinuria and in the total number of lymphocytes, T cells, and HLA-DR+- activated T cells. Moreover, the patient became sensitive to steroids and RTX. LCAP reduced circulating immune cells including activated T cells and could be effective in treating rituximab-resistant nephrotic syndrome and SRNS and in achieving remission of proteinuria.
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Affiliation(s)
- Maiko Takakura
- Department of Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Masaki Shimizu
- Department of Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Mao Mizuta
- Department of Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Natsumi Inoue
- Department of Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Yuko Tasaki
- Department of Pediatrics, Kanazawa Medical Center, National Hospital Organization, 1-1 Shimo-ishibiki, Kanazawa, Japan
| | - Kazuhide Ohta
- Department of Pediatrics, Kanazawa Medical Center, National Hospital Organization, 1-1 Shimo-ishibiki, Kanazawa, Japan
| | - Kengo Furuichi
- Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan
| | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akihiro Yachie
- Department of Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
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Tsuji S, Kimata T, Yamanouchi S, Kitao T, Kino J, Suruda C, Kaneko K. Regulatory T cells and CTLA-4 in idiopathic nephrotic syndrome. Pediatr Int 2017; 59:643-646. [PMID: 28544686 DOI: 10.1111/ped.13255] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 12/28/2016] [Accepted: 01/31/2017] [Indexed: 12/28/2022]
Abstract
The pathogenesis of idiopathic nephrotic syndrome (INS) remains unknown. Recently, it was postulated that suppression of regulatory T cells (Treg) leads to massive proteinuria in INS, although there is some controversy. Considering the important role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in Treg-mediated immune suppression, the aim of this study was therefore to clarify the involvement of Treg and CTLA-4 in the pathogenesis of INS. Fifteen patients with INS were enrolled. Their blood was sampled twice, once at onset and once at remission induced by glucocorticoid. Although median Treg number was significantly lower at onset than in healthy children, it increased at remission. Similarly, serum CTLA-4 concentration significantly increased at remission compared with onset. Furthermore, a positive significant correlation was observed between Treg number and serum CTLA-4 level. This suggests that Treg and CTLA-4 are involved in the induction of remission in INS.
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Affiliation(s)
- Shoji Tsuji
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Takahisa Kimata
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | | | - Tetsuya Kitao
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Jiro Kino
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Chikushi Suruda
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Kazunari Kaneko
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
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Madanchi N, Bitzan M, Takano T. Rituximab in Minimal Change Disease: Mechanisms of Action and Hypotheses for Future Studies. Can J Kidney Health Dis 2017; 4:2054358117698667. [PMID: 28540057 PMCID: PMC5433659 DOI: 10.1177/2054358117698667] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Accepted: 11/23/2016] [Indexed: 12/13/2022] Open
Abstract
Treatment with rituximab, a monoclonal antibody against the B-lymphocyte surface protein CD20, leads to the depletion of B cells. Recently, rituximab was reported to effectively prevent relapses of glucocorticoid-dependent or frequently relapsing minimal change disease (MCD). MCD is thought to be T-cell mediated; how rituximab controls MCD is not understood. In this review, we summarize key clinical studies demonstrating the efficacy of rituximab in idiopathic nephrotic syndrome, mainly MCD. We then discuss immunological features of this disease and potential mechanisms of action of rituximab in its treatment based on what is known about the therapeutic action of rituximab in other immune-mediated disorders. We believe that studies aimed at understanding the mechanisms of action of rituximab in MCD will provide a novel approach to resolve the elusive immune pathophysiology of MCD.
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Affiliation(s)
- Nima Madanchi
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
| | - Martin Bitzan
- Division of Nephrology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada
| | - Tomoko Takano
- Division of Nephrology, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
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Benign acute childhood myositis complicating influenza B infection in a boy with idiopathic nephrotic syndrome. Cent Eur J Immunol 2016; 41:328-331. [PMID: 27833453 PMCID: PMC5099392 DOI: 10.5114/ceji.2016.63135] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 09/09/2016] [Indexed: 12/19/2022] Open
Abstract
Introduction Benign acute childhood myositis (BACM) is an acute complication of an infection characterized by calf pain, limitation of lower limb mobility, an increase in serum creatine kinase, and a self-limiting course. No reports of BACM in children with idiopathic nephrotic syndrome (INS) can be found in the literature. Case report A 5-year-old boy with steroid-sensitive INS presented with fever, leg pain, and problems with walking. Physical examination showed pharyngeal erythema, preserved movements in all joints, and weakness of leg muscles. Laboratory tests showed white blood cell count 3900/µl, albumin 2.3 g/dl, urea 25 mg/dl, creatinine 0.3 mg/dl, increased transaminases (AspAT 440 U/l, AlAT 100 U/l) and creatine kinase (10 817 U/l), and proteinuria 3500 mg/dl. The boy was diagnosed with an INS bout and BACM. Testing for infective causes of myositis showed evidence of an influenza B virus infection. Treatment included prednisone and oseltamivir. A rapid improvement of motor function was observed, with normalization of serum creatine kinase and transaminases, and resolution of proteinuria. Conclusions 1. As influenza virus infection in a child with INS is a risk factor for complications and a disease bout, these patients should be vaccinated against influenza. 2. Differential diagnosis of leg pain and mobility limitation in a child with INS should include lower limb deep venous thrombosis, arthritis, post-infectious neurological complications (including Guillain-Barré syndrome), and BACM. 3. Serum creatine kinase level should be measured in all cases of motor disturbances in a child with symptoms of respiratory tract infection.
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Prasad N, Jaiswal AK, Agarwal V, Yadav B, Sharma RK, Rai M, Singh H, Chaturvedi S, Singh A. Differential alteration in peripheral T-regulatory and T-effector cells with change in P-glycoprotein expression in Childhood Nephrotic Syndrome: A longitudinal study. Cytokine 2015; 72:190-196. [PMID: 25661194 DOI: 10.1016/j.cyto.2014.12.028] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 12/15/2014] [Accepted: 12/31/2014] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Childhood Idiopathic Nephrotic Syndrome (INS) responds to glucocorticoid therapy, however, 60-80% of patients relapse and some of them become steroid non responsive. INS may occur because of T cell dysfunction, abnormal cytokines and podocytopathies which reverse on steroid treatment. The reason of relapses could be imbalances in T cells phenotypes and respective cytokines. Herein, we hypothesize that relapses in INS may occur due to imbalance in T-regulatory and T-effector cell with their respective cytokines and overexpression of P-gp on lymphocytes. METHODS The frequency of peripheral blood CD4(+)CD25(+)FoxP3(+) Treg, CD4(+)IFN-γ(+) Th1 and CD4(+)IL-4(+) Th2 lymphocytes and their respective cytokines and P-gp expression on peripheral blood lymphocytes (PBLs) were analyzed in INS patients at baseline (n=26), during remission (n=24) and at relapse (n=15). RESULTS Compared to baseline, the frequency of Tregs was significantly increased at remission and decreased during relapse. In contrast, the frequency of Th1 and Th2 lymphocytes was significantly decreased during remission and increased at the time of relapse. Similarly, expression of P-gp was significantly high at baseline and at the time of relapse as compared to remission. Levels of cytokines IL-10 and TGF-β in the supernatant of stimulated PBMCs was increased during remission and decreased during relapse. In contrast, levels of IFN-γ and IL-4 were decreased during remission and increased at the time of relapse. CONCLUSIONS Steroid therapy in INS induces decreased P-gp expression on PBLs along with increased frequency and cytokine response of T-regulatory cells, and reduced frequency and respective cytokine response of Th1 and Th2 cells during remission. However, reversal in the frequency and respective cytokines of T-regs, Th1 and Th2, and P-gp expression on PBLs occurs during relapses on follow-up.
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Affiliation(s)
- Narayan Prasad
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
| | - Akhilesh K Jaiswal
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Vikas Agarwal
- Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Brijesh Yadav
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Raj Kumar Sharma
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Mohit Rai
- Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Harshit Singh
- Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Saurabh Chaturvedi
- Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Ajay Singh
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Abstract
Viral infections associate temporally with the onset of many glomerular diseases, particularly in children. In other cases of glomerulonephritis, when infection is clinically silent, viral syndromes can still be implicated as a trigger. However, strong evidence for viral causality in most glomerular disease is still lacking. While numerous case reports in children document the occurrence of specific forms of glomerular disease after seroconversion to a wide range of viruses, relatively few reports provide pathologic evidence of viral infection associated with glomerular lesions on kidney biopsy. Strong associations between hepatitis viruses and glomerular injury have been acknowledged in adults, but hepatitis C virus appears not to be an etiology in children. In the context of treating glomerular diseases, when diagnosed, the treatment of hepatitis B virus, cytomegalovirus and human immunodeficiency virus in children with membranoproliferative, membranous and collapsing glomerulopathy plays an important role. Otherwise, there is no evidence suggesting that the identification of a viral infection in a child with glomerulopathy should change the management of the infection or the glomerulonephritis. Therefore, additional research into this topic is very much needed.
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13
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Jaiswal A, Prasad N, Agarwal V, Yadav B, Tripathy D, Rai M, Nath M, Sharma RK, Modi DR. Regulatory and effector T cells changes in remission and resistant state of childhood nephrotic syndrome. Indian J Nephrol 2014; 24:349-355. [PMID: 25484527 PMCID: PMC4244713 DOI: 10.4103/0971-4065.132992] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Idiopathic minimal change disease is a disorder of T-cell dysfunction. The relative predominance of regulatory T cells (Tregs), Th1, and Th2 cells in nephrotic syndrome (NS) remains controversial. Imbalance in peripheral blood regulatory and effector T cells (Teff) are linked to cell mediated immune response and may be associated with steroid response in NS. Peripheral blood CD4 + CD25 + FoxP3 + (Tregs), CD4 + IFN-γ(+) (Th1), and CD4 + IL-4 + (Th2) lymphocytes were analyzed in 22 steroid-sensitive NS (SSNS) patients in sustained remission, 21 steroid-resistant NS (SRNS) and 14 healthy controls. The absolute percentage values and ratio of Th1/Tregs, Th2/Tregs, and Th1/Th2 were compared between SSNS, SRNS and control subjects. The percentage of Tregs was lower in SRNS patients (P = 0.001) compared with that of SSNS and healthy control. The percentage of Th1 cells was higher in SRNS (P = 0.001) compared to that of SSNS patients; however, it was similar to healthy controls (P = 1.00). The percentage of Th2 cells in SRNS (P = 0.001) was higher as compared to SSNS and controls. The ratio of Th1/Treg cells in SRNS (P = 0.001) was higher as compared to SSNS patients and controls. The ratio of Th2/Treg was also higher in SRNS as compared to SSNS and controls. The ratio of Th1/Th2 cells in SSNS, SRNS, and healthy controls were similar. The cytokines secretion complemented the change in different T-cell subtypes in SSNS, SRNS and healthy controls. However, the IFN-γ secretion in healthy controles was low inspite of similar percentage of Th1 cells among SRNS cases. We conclude that greater ratio of Tregs compared to that Th1 and Th2 favor steroid sensitivity and reverse ratio results in to SRNS. The difference in ratio is related to pathogenesis or it can be used as marker to predict steroid responsiveness needs further evaluation.
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Affiliation(s)
- A. Jaiswal
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - N. Prasad
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - V. Agarwal
- Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - B. Yadav
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - D. Tripathy
- Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - M. Rai
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - M. Nath
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - R. K. Sharma
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - D. R. Modi
- Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, Uttar Pradesh, India
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