1
|
Robinson CH, Smoyer WE, Cara-Fuentes G. Unraveling the Immunogenetic Mechanisms of Childhood Idiopathic Nephrotic Syndrome. J Pediatr 2025; 282:114595. [PMID: 40252964 DOI: 10.1016/j.jpeds.2025.114595] [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: 01/20/2025] [Revised: 03/16/2025] [Accepted: 04/14/2025] [Indexed: 04/21/2025]
Affiliation(s)
- Cal H Robinson
- Division of Nephrology, The Hospital for Sick Children, Toronto, ON, Canada; Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.
| | - William E Smoyer
- The Center for Clinical and Translational Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH; Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH
| | - Gabriel Cara-Fuentes
- Kidney and Urinary Tract Center, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH
| |
Collapse
|
2
|
Cozzo D, Orlando F, Bruno M, Ogna A, Forni Ogna V. Minimal change glomerular disease associated with solid neoplasms: a systematic review. J Nephrol 2025; 38:343-352. [PMID: 39352607 PMCID: PMC11961479 DOI: 10.1007/s40620-024-02084-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 08/16/2024] [Indexed: 04/03/2025]
Abstract
BACKGROUND Paraneoplastic minimal change disease (MCD) has been associated with hematological malignancies, whereas solid malignancies are commonly associated with membranous glomerulonephritis. In this systematic review of the literature, we describe the clinical features, treatment and outcome of MCD associated with solid neoplasms. METHODS We performed a systematic review of the MEDLINE, COCHRANE, EMBASE and SCOPUS databases, including case reports of adult patients with biopsy-proven MCD and solid malignancy, without language or time restrictions. RESULTS Sixty-seven papers were included, presenting 86 cases with a mean age of 57.8 ± 14.7 years; 41.0% were women. Nephrotic syndrome was the initial presentation in 96.2% of patients; 67.2% had kidney function impairment, and 21.2% required kidney replacement therapy. The most frequent malignancies were malignant thymoma (34.9%), kidney (14.0%), lung (12.8%), and gastrointestinal tumors (12.8%). In 40.7% of cases, the neoplasm diagnosis preceded MCD by 33.8 ± 46.1 months, while in 31.4%, it followed diagnosis of MCD by 12.4 ± 22.6 months. In 27.9%, the neoplasm and kidney disease were diagnosed simultaneously. Immunosuppressive therapy was started in 79.1% of cases and tumor-specific treatment in 83.7%. Remission of MCD was achieved in 80.2% of patients: 38.2% responded to immunosuppressive treatment alone and 29.6% to oncological treatment alone. CONCLUSIONS The association between MCD and solid neoplasms is well-documented. Immunosuppressive therapy alone induced nephrotic syndrome remission in over one-third of cases; most others responded to tumor-specific treatment. Solid tumor screening should be considered in MCD independently of the steroid response, though more data on solid tumor-associated MCD prevalence are needed for a definitive statement. PROSPERO TRIAL REGISTRATION NUMBER CRD42024521854.
Collapse
Affiliation(s)
- Domenico Cozzo
- Servizio di nefrologia, EOC Ospedale "La Carità", Locarno, Switzerland
| | - Francesca Orlando
- Servizio di medicina interna, EOC Ospedale "La Carità", Locarno, Switzerland
| | - Mariolina Bruno
- Servizio di medicina interna, EOC Ospedale "La Carità", Locarno, Switzerland
| | - Adam Ogna
- Servizio di medicina interna, EOC Ospedale "La Carità", Locarno, Switzerland
- Faculty of Biomedical Sciences, Università Della Svizzera Italiana, Lugano, Switzerland
| | - Valentina Forni Ogna
- Servizio di nefrologia, EOC Ospedale "La Carità", Locarno, Switzerland.
- Faculty of Biomedical Sciences, Università Della Svizzera Italiana, Lugano, Switzerland.
| |
Collapse
|
3
|
Sun Y, Li Z, Sun J, Zhang S, Wang R, Chen B. The efficacy and safety of rituximab with or without glucocorticoid in inducing remission of MCD with different clinical presentations in adults: a retrospective study. Clin Kidney J 2024; 17:sfae139. [PMID: 38854425 PMCID: PMC11161702 DOI: 10.1093/ckj/sfae139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Indexed: 06/11/2024] Open
Abstract
Background To investigate the efficacy and safety of rituximab (RTX) with or without glucocorticoid (GC) in inducing remission of minimal change disease (MCD) in adults. Methods Twenty-one adult MCD patients were included in the study. The patients were assigned to the following three groups according to their background before RTX treatment: an RTX single drug direct induction treatment group (Group A; n = 9), a short-term, low-dose GC combined with RTX induction treatment group (Group B; n = 4), and a short-term, adequate-dose GC-induced remission and RTX maintenance treatment group (Group C; n = 8). The primary endpoints were the time to induction of remission and the rate of clinical remission at 12 months. Results All patients achieved clinical remission, with 19 (90.48%) achieving complete remission (CR), and the median remission time was 4 (2.5, 12) weeks. Eight (88.89%) patients in Group A achieved CR, and the median remission time was 3 (2.25, 14) weeks. In Group B, three (75.00%) patients achieved CR, with a median remission time of 4 (4, 10) weeks. In Group C, eight (100.00%) patients achieved CR, and the median remission time was 3.5 (2, 4) weeks. Conclusions In MCD patients without acute kidney injury, adequate RTX alone or short-term combined treatment with low-dose GCs can effectively induce and maintain MCD remission. Adequate short-term GCs combined with RTX maintenance may be an effective alternative for MCD patients in context of acute kidney injury. There is a need to investigate different induction therapy regimens for the remission of MCD patients with different backgrounds.
Collapse
Affiliation(s)
- Yujiao Sun
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Zhuo Li
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Jing Sun
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Shasha Zhang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Bing Chen
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| |
Collapse
|
4
|
Chugh SS, Clement LC. "Idiopathic" minimal change nephrotic syndrome: a podocyte mystery nears the end. Am J Physiol Renal Physiol 2023; 325:F685-F694. [PMID: 37795536 PMCID: PMC10878723 DOI: 10.1152/ajprenal.00219.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/11/2023] [Accepted: 10/02/2023] [Indexed: 10/06/2023] Open
Abstract
The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human minimal change nephrotic syndrome (MCNS). Recently, uncovered genomic defects upstream of ZHX2 induce a ZHX2 hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In ZHX2 hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4Rα. During disease relapse, high plasma soluble IL-4Rα (sIL-4Rα) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4Rα toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of ANGPTL4, resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hyposialylated ANGPTL4, and hyposialylation-related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human minimal change disease (MCD), including massive and selective proteinuria, podocyte foot process effacement, and loss of glomerular basement membrane charge. Administration of glucocorticoids reduces ANGPTL4 upregulation, which reduces hyposialylation injury to improve the clinical phenotype. Improving sialylation of podocyte-secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-α, IL-6, or sIL-4Rα after the induction of the cytokine storm in Zhx2 hypomorph mice reduces albuminuria, suggesting potential new therapeutic targets for clinical trials to prevent MCD relapse. These studies collectively lay to rest prior suggestions of a role of single cytokines or soluble proteins in triggering MCD relapse.
Collapse
Affiliation(s)
- Sumant S Chugh
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States
| | - Lionel C Clement
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States
| |
Collapse
|
5
|
Miao J, Krisanapan P, Tangpanithandee S, Thongprayoon C, Mao MA, Cheungpasitporn W. Efficacy of extracorporeal plasma therapy for adult native kidney patients with Primary FSGS: a Systematic review. Ren Fail 2023; 45:2176694. [PMID: 36762994 PMCID: PMC9930861 DOI: 10.1080/0886022x.2023.2176694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
PURPOSE This study aimed to assess efficacy of extracorporeal plasma therapy (EPT), including plasmapheresis (PE), immunoadsorption (IA), low-density lipoprotein apheresis (LDL-A), and lymphocytapheresis (LCAP) for adult native kidney patients with primary focal segmental glomerulosclerosis (FSGS). METHODS A literature search was conducted using MEDLINE, EMBASE and Cochrane Databases through August 2022. Studies that reported outcomes of EPT in adult native kidneys with primary FSGS were enrolled. RESULTS 18 studies with 104 therapy-resistant or refractory primary native FSGS patients were identified. Overall EPT response rate was 56%, with long-term benefit of 46%. Of the 101 non-hemodialysis (HD) patients, 54% achieved remission, with 30% complete remission (CR) and 23% partial remission (PR). Of 31 patients with PE, response rate was 65%; CR and PR rates were 27% and 37% in 30 non-HD patients. Of 61 patients with LDL-A, the response rate was 54%; CR and PR rates were 41% and 3% in 29 non-HD patients. Of 10 patients with IA, response rate was 40%. Of 2 patients with LCAP, 1 achieved CR, and one developed renal failure. All 3 HD patients showed increase in urine output and gradual decrease in urine protein excretion following PE (n = 1) or LDL-A (n = 2). 2 of 3 HD patients ultimately discontinued dialysis. CONCLUSION EPT with immunosuppressive therapy showed benefit in some patients with refractory primary FSGS, and PE appeared to have a higher response rate.
Collapse
Affiliation(s)
- Jing Miao
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA,CONTACT Jing Miao Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Pajaree Krisanapan
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA,Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand,Division of Nephrology, Department of Internal Medicine, Thammasat University Hospital, Pathum Thani, Thailand
| | - Supawit Tangpanithandee
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Charat Thongprayoon
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Michael A. Mao
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Wisit Cheungpasitporn
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
6
|
Salfi G, Casiraghi F, Remuzzi G. Current understanding of the molecular mechanisms of circulating permeability factor in focal segmental glomerulosclerosis. Front Immunol 2023; 14:1247606. [PMID: 37795085 PMCID: PMC10546017 DOI: 10.3389/fimmu.2023.1247606] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 09/05/2023] [Indexed: 10/06/2023] Open
Abstract
The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated. However, a growing body of evidence emphasizes the pivotal role of the immune system in both initiating and perpetuating the disease. Extensive investigations, encompassing both experimental models and patient studies, have implicated T cells, B cells, and complement as crucial actors in the pathogenesis of primary FSGS, with various molecules being proposed as potential "circulating factors" contributing to the disease and its recurrence post kidney-transplantation. In this review, we critically assessed the existing literature to identify essential pathways for a comprehensive characterization of the pathogenesis of FSGS. Recent discoveries have shed further light on the intricate interplay between these mechanisms. We present an overview of the current understanding of the engagement of distinct molecules and immune cells in FSGS pathogenesis while highlighting critical knowledge gaps that require attention. A thorough characterization of these intricate immune mechanisms holds the potential to identify noninvasive biomarkers that can accurately identify patients at high risk of post-transplant recurrence. Such knowledge can pave the way for the development of targeted and personalized therapeutic approaches in the management of FSGS.
Collapse
Affiliation(s)
| | - Federica Casiraghi
- Istituto di Ricerche Farmacologiche Mario Negri Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Bergamo, Italy
| | | |
Collapse
|
7
|
Vincenti F, Angeletti A, Ghiggeri GM. State of the art in childhood nephrotic syndrome: concrete discoveries and unmet needs. Front Immunol 2023; 14:1167741. [PMID: 37503337 PMCID: PMC10368981 DOI: 10.3389/fimmu.2023.1167741] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/21/2023] [Indexed: 07/29/2023] Open
Abstract
Nephrotic syndrome (NS) is a clinical entity characterized by proteinuria, hypoalbuminemia, and peripheral edema. NS affects about 2-7 per 100,000 children aged below 18 years old yearly and is classified, based on the response to drugs, into steroid sensitive (SSNS), steroid dependent, (SDNS), multidrug dependent (MDNS), and multidrug resistant (MRNS). Forms of NS that are more difficult to treat are associated with a worse outcome with respect to renal function. In particular, MRNS commonly progresses to end stage renal failure requiring renal transplantation, with recurrence of the original disease in half of the cases. Histological presentations of NS may vary from minimal glomerular lesions (MCD) to focal segmental glomerulosclerosis (FSGS) and, of relevance, the histological patterns do not correlate with the response to treatments. Moreover, around half of MRNS cases are secondary to causative pathogenic variants in genes involved in maintaining the glomerular structure. The pathogenesis of NS is still poorly understood and therapeutic approaches are mostly based on clinical experience. Understanding of pathogenetic mechanisms of NS is one of the 'unmet needs' in nephrology and represents a significant challenge for the scientific community. The scope of the present review includes exploring relevant findings, identifying unmet needs, and reviewing therapeutic developments that characterize NS in the last decades. The main aim is to provide a basis for new perspectives and mechanistic studies in NS.
Collapse
Affiliation(s)
- Flavio Vincenti
- Division of Nephrology, Department of Medicine and Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Andrea Angeletti
- Nephrology Dialysis and Transplantation, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
| | - Gian Marco Ghiggeri
- Nephrology Dialysis and Transplantation, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
| |
Collapse
|
8
|
Abstract
Idiopathic nephrotic syndrome often responds to immunosuppressive treatment. Nevertheless, this syndrome-and the drugs used to treat it-remain important causes of patient morbidity. Idiopathic nephrotic syndrome is usually caused by minimal change disease or FSGS, diseases that primarily affect the podocytes. In spite of decades of research, the underlying causes of both diseases remain incompletely understood. There is, however, a large body of observational and experimental data linking the immune system with both minimal change disease and FSGS, including associations with systemic infections and hematologic malignancies. Perhaps most compellingly, many different immunomodulatory drugs are effective for treating idiopathic nephrotic syndrome, including biologic agents that have well-defined immune targets. In fact, the unexpected efficacy of targeted therapeutic agents has provided important new insights into the pathogenesis of these diseases. Given the large number of drugs that are available to deplete or block specific cells and molecules within the immune system, a better understanding of the immunologic causes of idiopathic nephrotic syndrome may lead to better diagnostic and therapeutic approaches.
Collapse
Affiliation(s)
- Ruth E. Campbell
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, Colorado
| | - Joshua M. Thurman
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, Colorado
| |
Collapse
|
9
|
Shen Q, Teng L, Wang Y, Guo L, Xu F, Huang H, Xie W, Zhou Q, Chen Y, Wang J, Mao Y, Chen J, Jiang H. Integrated genomic, transcriptomic and metabolomic analysis reveals MDH2 mutation-induced metabolic disorder in recurrent focal segmental glomerulosclerosis. Front Immunol 2022; 13:962986. [PMID: 36159820 PMCID: PMC9495259 DOI: 10.3389/fimmu.2022.962986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/29/2022] [Indexed: 11/13/2022] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) has an over 30% risk of recurrence after kidney transplantation (Ktx) and is associated with an extremely high risk of graft loss. However, mechanisms remain largely unclear. Thus, this study identifies novel genes related to the recurrence of FSGS (rFSGS). Whole genome-wide sequencing and next-generation RNA sequencing were used to identify the candidate mutant genes associated with rFSGS in peripheral blood mononuclear cells (PBMCs) from patients with biopsy-confirmed rFSGS after KTx. To confirm the functional role of the identified gene with the MDH2 c.26C >T mutation, a homozygous MDH2 c.26C >T mutation in HMy2.CIR cell line was induced by CRISPR/Cas9 and co-cultured with podocytes, mesangial cells, or HK2 cells, respectively, to detect the potential pathogenicity of the c.26C >T variant in MDH2. A total of 32 nonsynonymous single nucleotide polymorphisms (SNPs) and 610 differentially expressed genes (DEGs) related to rFSGS were identified. DEGs are mainly enriched in the immune and metabolomic-related pathways. A variant in MDH2, c.26C >T, was found in all patients with rFSGS, which was also accompanied by lower levels of mRNA expression in PBMCs from relapsed patients compared with patients with remission after KTx. Functionally, co-cultures of HMy2.CIR cells overexpressing the mutant MDH2 significantly inhibited the expression of synaptopodin, podocin, and F-actin by podocytes compared with those co-cultured with WT HMy2.CIR cells or podocytes alone. We identified that MDH2 is a novel rFSGS susceptibility gene in patients with recurrence of FSGS after KTx. Mutation of the MDH2 c.26C >T variant may contribute to progressive podocyte injury in rFSGS patients.
Collapse
Affiliation(s)
- Qixia Shen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Institute of Nephrology, Zhejiang University, Hangzhou, China
| | - Lisha Teng
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Institute of Nephrology, Zhejiang University, Hangzhou, China
| | - Yucheng Wang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Institute of Nephrology, Zhejiang University, Hangzhou, China
| | - Luying Guo
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Institute of Nephrology, Zhejiang University, Hangzhou, China
| | - Feng Xu
- The Centre for Heart and Lung Innovation, The University of British Columbia, Vancouver, BC, Canada
| | - Hongfeng Huang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Institute of Nephrology, Zhejiang University, Hangzhou, China
| | - Wenqing Xie
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Institute of Nephrology, Zhejiang University, Hangzhou, China
| | - Qin Zhou
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Institute of Nephrology, Zhejiang University, Hangzhou, China
| | - Ying Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Institute of Nephrology, Zhejiang University, Hangzhou, China
| | - Junwen Wang
- Department of Health Sciences Research and Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ, United States
| | - Youying Mao
- Dapartment of Nephrology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Institute of Nephrology, Zhejiang University, Hangzhou, China
| | - Hong Jiang
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
- Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, China
- Zhejiang Clinical Research Center of Kidney and Urinary System Disease, Hangzhou, China
- Institute of Nephrology, Zhejiang University, Hangzhou, China
- *Correspondence: Hong Jiang,
| |
Collapse
|
10
|
Seitz-Polski B, Audard V, Ghiggeri GM, Tomas NM. Editorial: Immune dysfunction in nephrotic syndrome - recent advances and new roads ahead. Front Immunol 2022; 13:985925. [PMID: 35983048 PMCID: PMC9379314 DOI: 10.3389/fimmu.2022.985925] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 07/13/2022] [Indexed: 11/17/2022] Open
Affiliation(s)
- Barbara Seitz-Polski
- Centre de Référence Maladies Rares Syndrome Néphrotique Idiopathique, CHU de Nice, Université Côte d’Azur, Nice, France
- Unité de Recherche Clinique de la Côte d’Azur (UR2CA), Université Côte d’Azur, Nice, France
- Laboratoire d’Immunologie, CHU de Nice, Université Côte d’Azur, Nice, France
- Service de Néphrologie-Dialyse-Transplantation, CHU de Nice, Université Côte d’Azur, Nice, France
- *Correspondence: Barbara Seitz-Polski, ; Vincent Audard, ;Gian Marco Ghiggeri, ; Nicola M. Tomas,
| | - Vincent Audard
- Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri-Mondor, Service de Néphrologie et Transplantation, Centre de Référence Maladie Rare “Syndrome Néphrotique Idiopathique”, Fédération Hospitalo-Universitaire, Innovative Therapy for Immune Disorders, Créteil, France
- Univ Paris Est Créteil, Institut National de la Santé et de la Recherche Médicale (INSERM) U955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil, France
- *Correspondence: Barbara Seitz-Polski, ; Vincent Audard, ;Gian Marco Ghiggeri, ; Nicola M. Tomas,
| | - Gian Marco Ghiggeri
- Laboratory on Molecular Medicine, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
- Division of Nephrology, Dialysis, Transplantation, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
- *Correspondence: Barbara Seitz-Polski, ; Vincent Audard, ;Gian Marco Ghiggeri, ; Nicola M. Tomas,
| | - Nicola M. Tomas
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- *Correspondence: Barbara Seitz-Polski, ; Vincent Audard, ;Gian Marco Ghiggeri, ; Nicola M. Tomas,
| |
Collapse
|
11
|
Protective effects of rituximab on puromycin-induced apoptosis, loss of adhesion and cytoskeletal alterations in human podocytes. Sci Rep 2022; 12:12297. [PMID: 35853959 PMCID: PMC9296604 DOI: 10.1038/s41598-022-16333-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/08/2022] [Indexed: 11/08/2022] Open
Abstract
Podocytes are highly specialized cells playing a key role in the filtration function of the kidney. A damaged podocyte ultrastructure is associated with a reorganization of the actin cytoskeleton and accompanied with a loss of adhesion to the glomerular basement membrane leading to proteinuria in many forms of glomerular diseases, e.g. nephrotic syndrome. If the first-line therapy with glucocorticoids fails, alternative immunosuppressive agents are used, which are known to have the potential to stabilize the actin cytoskeleton. A new option for preventing relapses in steroid dependent nephrotic syndrome is the monoclonal antibody rituximab, which, in addition to its B-cell depleting effect, is assumed to have direct effects on podocytes. We here provide data on the non-immunological off-target effects of the immunosuppressant rituximab on podocyte structure and dynamics in an in vitro puromycin aminonucleoside model of podocyte injury. A conditionally immortalized human podocyte cell line was used. Differentiated podocytes were treated with puromycin aminonucleoside and rituximab. Our studies focussed on analyzing the structure of the actin cytoskeleton, cellular adhesion and apoptosis using immunofluorescence staining and protein biochemistry methods. Treatment with rituximab resulted in a stabilization of podocyte actin stress fibers in the puromycin aminonucleoside model, leading to an improvement in cell adhesion. A lower apoptosis rate was observed after parallel treatment with puromycin aminonucleoside and rituximab visualized by reduced nuclear fragmentation. Consistent with this data, Western-blot analyses demonstrated that rituximab directly affects the caspase pathways by inhibiting the activation of Caspases-8, -9 and -3, suggesting that rituximab may inhibit apoptosis. In conclusion, our results indicate an important role of the immunosuppressant rituximab in terms of stability and morphogenesis of podocytes, involving apoptosis pathways. This could help to improve therapeutical concepts for patients with proteinuria mediated by diseased podocytes.
Collapse
|
12
|
Potential contribution of the immune system to the emergence of renal diseases. Immunol Lett 2022; 248:1-6. [DOI: 10.1016/j.imlet.2022.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 06/04/2022] [Indexed: 11/21/2022]
|
13
|
Guzmán Morais B, Ordóñez Álvarez FÁ, Santos Rodríguez F, Martín Ramos S, Fernández Novo G. Rituximab treatment in pediatric patients with steroid-dependent nephrotic syndrome: A tertiary hospital. ANALES DE PEDIATRÍA (ENGLISH EDITION) 2022; 96:83-90. [DOI: 10.1016/j.anpede.2020.12.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 12/09/2020] [Indexed: 11/16/2022] Open
|
14
|
Purohit S, Piani F, Ordoñez FA, de Lucas-Collantes C, Bauer C, Cara-Fuentes G. Molecular Mechanisms of Proteinuria in Minimal Change Disease. Front Med (Lausanne) 2022; 8:761600. [PMID: 35004732 PMCID: PMC8733331 DOI: 10.3389/fmed.2021.761600] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/15/2021] [Indexed: 11/13/2022] Open
Abstract
Minimal change disease (MCD) is the most common type of idiopathic nephrotic syndrome in childhood and represents about 15% cases in adults. It is characterized by massive proteinuria, edema, hypoalbuminemia, and podocyte foot process effacement on electron microscopy. Clinical and experimental studies have shown an association between MCD and immune dysregulation. Given the lack of inflammatory changes or immunocomplex deposits in the kidney tissue, MCD has been traditionally thought to be mediated by an unknown circulating factor(s), probably released by T cells that directly target podocytes leading to podocyte ultrastructural changes and proteinuria. Not surprisingly, research efforts have focused on the role of T cells and podocytes in the disease process. Nevertheless, the pathogenesis of the disease remains a mystery. More recently, B cells have been postulated as an important player in the disease either by activating T cells or by releasing circulating autoantibodies against podocyte targets. There are also few reports of endothelial injury in MCD, but whether glomerular endothelial cells play a role in the disease remains unexplored. Genome-wide association studies are providing insights into the genetic susceptibility to develop the disease and found a link between MCD and certain human haplotype antigen variants. Altogether, these findings emphasize the complex interplay between the immune system, glomerular cells, and the genome, raising the possibility of distinct underlying triggers and/or mechanisms of proteinuria among patients with MCD. The heterogeneity of the disease and the lack of good animal models of MCD remain major obstacles in the understanding of MCD. In this study, we will review the most relevant candidate mediators and mechanisms of proteinuria involved in MCD and the current models of MCD-like injury.
Collapse
Affiliation(s)
- Shrey Purohit
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Pediatrics, Section of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, United States
| | - Federica Piani
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Medicine and Surgery Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Flor A Ordoñez
- Division of Pediatric Nephrology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | | | - Colin Bauer
- Department of Pediatrics, Section of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, United States
| | - Gabriel Cara-Fuentes
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Pediatrics, Section of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, United States
| |
Collapse
|
15
|
Hackl A, Zed SEDA, Diefenhardt P, Binz-Lotter J, Ehren R, Weber LT. The role of the immune system in idiopathic nephrotic syndrome. Mol Cell Pediatr 2021; 8:18. [PMID: 34792685 PMCID: PMC8600105 DOI: 10.1186/s40348-021-00128-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
Idiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia and usually responds well to steroids. However, relapses are frequent, which can require multi-drug therapy with deleterious long-term side effects. In the last decades, different hypotheses on molecular mechanisms underlying INS have been proposed and several lines of evidences strongly indicate a crucial role of the immune system in the pathogenesis of non-genetic INS. INS is traditionally considered a T-cell-mediated disorder triggered by a circulating factor, which causes the impairment of the glomerular filtration barrier and subsequent proteinuria. Additionally, the imbalance between Th17/Tregs as well as Th2/Th1 has been implicated in the pathomechanism of INS. Interestingly, B-cells have gained attention, since rituximab, an anti-CD20 antibody demonstrated a good therapeutic response in the treatment of INS. Finally, recent findings indicate that even podocytes can act as antigen-presenting cells under inflammatory stimuli and play a direct role in activating cellular pathways that cause proteinuria. Even though our knowledge on the underlying mechanisms of INS is still incomplete, it became clear that instead of a traditionally implicated cell subset or one particular molecule as a causative factor for INS, a multi-step control system including soluble factors, immune cells, and podocytes is necessary to prevent the occurrence of INS. This present review aims to provide an overview of the current knowledge on this topic, since advances in our understanding of the immunopathogenesis of INS may help drive new tailored therapeutic approaches forward.
Collapse
Affiliation(s)
- Agnes Hackl
- Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. .,Department of Internal Medicine II and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
| | - Seif El Din Abo Zed
- Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.,Department of Internal Medicine II and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Paul Diefenhardt
- Department of Internal Medicine II and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Julia Binz-Lotter
- Department of Internal Medicine II and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Rasmus Ehren
- Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Lutz Thorsten Weber
- Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| |
Collapse
|
16
|
Eroglu FK, Yazar V, Guler U, Yıldırım M, Yildirim T, Gungor T, Celikkaya E, Karakaya D, Turay N, Ciftci Dede E, Korkusuz P, Salih B, Bulbul M, Gursel I. Circulating extracellular vesicles of patients with steroid-sensitive nephrotic syndrome have higher RAC1 and induce recapitulation of nephrotic syndrome phenotype in podocytes. Am J Physiol Renal Physiol 2021; 321:F659-F673. [PMID: 34569252 DOI: 10.1152/ajprenal.00097.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Since previous research suggests a role of a circulating factor in the pathogenesis of steroid-sensitive nephrotic syndrome (NS), we speculated that circulating plasma extracellular vesicles (EVs) are a candidate source of such a soluble mediator. Here, we aimed to characterize and try to delineate the effects of these EVs in vitro. Plasma EVs from 20 children with steroid-sensitive NS in relapse and remission, 10 healthy controls, and 6 disease controls were obtained by serial ultracentrifugation. Characterization of these EVs was performed by electron microscopy, flow cytometry, and Western blot analysis. Major proteins from plasma EVs were identified via mass spectrometry. Gene Ontology classification analysis and Ingenuity Pathway Analysis were performed on selectively expressed EV proteins during relapse. Immortalized human podocyte culture was used to detect the effects of EVs on podocytes. The protein content and particle number of plasma EVs were significantly increased during NS relapse. Relapse NS EVs selectively expressed proteins that involved actin cytoskeleton rearrangement. Among these, the level of RAC-GTP was significantly increased in relapse EVs compared with remission and disease control EVs. Relapse EVs were efficiently internalized by podocytes and induced significantly enhanced motility and albumin permeability. Moreover, relapse EVs induced significantly higher levels of RAC-GTP and phospho-p38 and decreased the levels of synaptopodin in podocytes. Circulating relapse EVs are biologically active molecules that carry active RAC1 as cargo and induce recapitulation of the NS phenotype in podocytes in vitro.NEW & NOTEWORTHY Up to now, the role of extracellular vesicles (EVs) in the pathogenesis of steroid-sensitive nephrotic syndrome (NS) has not been studied. Here, we found that relapse NS EVs contain significantly increased active RAC1, induce enhanced podocyte motility, and increase expression of RAC-GTP and phospho-p38 expression in vitro. These results suggest that plasma EVs are biologically active molecules in the pathogenesis of NS.
Collapse
Affiliation(s)
- Fehime K Eroglu
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey.,SBU Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Volkan Yazar
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Ulku Guler
- Department of Chemistry, Hacettepe University, Ankara, Turkey
| | - Muzaffer Yıldırım
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Tugce Yildirim
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Tulin Gungor
- SBU Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Evra Celikkaya
- SBU Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Deniz Karakaya
- SBU Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Nilsu Turay
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| | - Eda Ciftci Dede
- Department of Histology and Embryology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Petek Korkusuz
- Department of Histology and Embryology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Bekir Salih
- Department of Chemistry, Hacettepe University, Ankara, Turkey
| | - Mehmet Bulbul
- SBU Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Ihsan Gursel
- Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
| |
Collapse
|
17
|
Seven novel podocyte autoantibodies were identified to diagnosis a new disease subgroup-autoimmune Podocytopathies. Clin Immunol 2021; 232:108869. [PMID: 34600127 DOI: 10.1016/j.clim.2021.108869] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/26/2021] [Accepted: 09/27/2021] [Indexed: 01/09/2023]
Abstract
Children with idiopathic nephrotic syndrome (INS) usually have podocyte injury, and recent studies suggest a B cell dysfunction in INS. Therefore, this study attempts to screen and identify the podocyte autoantibodies in patients. Two-dimensional electrophoresis and mass spectrometry were used to screen and identify the pathogenic podocyte autoantibodies in children with INS. The positive rate, expression pattern, and clinical correlation of these podocyte autoantibodies in children with INS were determined by clinical study. At least 66% of INS children have podocyte autoantibodies. Seven podocyte autoantibodies closely related to INS were screened and identified for the first time in this study. These podocyte autoantibodies are positively correlated with proteinuria, and its titer will decrease rapidly after effective treatment. In this study, a group of new disease subgroup-"autoimmune podocytes" were identified by podocyte autoantibodies.
Collapse
|
18
|
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.
Collapse
Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
| |
Collapse
|
19
|
Ye Q, Zhang Y, Zhuang J, Bi Y, Xu H, Shen Q, Liu J, Fu H, Wang J, Feng C, Tang X, Liu F, Gu W, Zhao F, Zhang J, Qin Y, Shang S, Shen H, Chen X, Shen H, Liu A, Xia Y, Lu Z, Shu Q, Mao J. The important roles and molecular mechanisms of annexin A 2 autoantibody in children with nephrotic syndrome. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1452. [PMID: 34734004 PMCID: PMC8506724 DOI: 10.21037/atm-21-3988] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/01/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUND In recent years, B-cell dysfunction has been found to play an important role in the pathogenesis of primary nephrotic syndrome (PNS). B cells play a pathogenic role by secreting antibodies against their target antigens after transforming into plasma cells. Therefore, this study aimed to screen the autoantibodies that cause PNS and explore their pathogenic mechanisms. METHODS Western blotting and mass spectrometry were employed to screen and identify autoantibodies against podocytes in children with PNS. Both in vivo and in vitro experiments were used to study the pathogenic mechanism of PNS. The results were confirmed in a large multicenter clinical study in children. RESULTS Annexin A2 autoantibody was highly expressed in children with PNS with a pathological type of minimal change disease (MCD) or focal segmental glomerulosclerosis without genetic factors. The mouse model showed that anti-Annexin A2 antibody could induce proteinuria in vivo. Mechanistically, the effect of Annexin A2 antibody on the Rho signaling pathway was realized through promoting the phosphorylation of Annexin A2 at Tyr24 on podocytes by reducing its binding to PTP1B, which led to the cytoskeletal rearrangement and damage of podocytes, eventually causing proteinuria and PNS. CONCLUSIONS Annexin A2 autoantibody may be responsible for some cases of PNS with MCD/FSGS in children.
Collapse
Affiliation(s)
- Qing Ye
- Department of Clinical Laboratory, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Yingying Zhang
- Department of Nephrology, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Jieqiu Zhuang
- Department of Pediatric Nephrology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ye Bi
- Department of Pediatric Nephrology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hong Xu
- Department of Nephrology, Children’s Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai, China
| | - Qian Shen
- Department of Nephrology, Children’s Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai, China
| | - Jialu Liu
- Department of Nephrology, Children’s Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai, China
| | - Haidong Fu
- Department of Nephrology, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Jingjing Wang
- Department of Nephrology, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Chunyue Feng
- Department of Nephrology, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Xiaoxiao Tang
- Department of Nephrology, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Fei Liu
- Department of Nephrology, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Weizhong Gu
- Department of Pathology, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Fei Zhao
- Department of Nephrology, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Jianjiang Zhang
- Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yuanhan Qin
- Department of Pediatric Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shiqiang Shang
- Department of Clinical Laboratory, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Hongqiang Shen
- Department of Clinical Laboratory, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Xuejun Chen
- Department of Clinical Laboratory, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Huijun Shen
- Department of Nephrology, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Aimin Liu
- Department of Nephrology, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Yonghui Xia
- Department of Nephrology, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Zhihong Lu
- Department of Nephrology, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Qiang Shu
- Department of Thoracic and Cardiovascular Surgery, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Jianhua Mao
- Department of Nephrology, The Children’s Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| |
Collapse
|
20
|
Liu D, Zhou Z, Wang M, Nie S, Li J, Hu B, He W, Wang G, Ai J. Extended infusion of rituximab combined with steroids is effective in inducing remission and reducing relapse in adult minimal change disease. BMC Nephrol 2021; 22:242. [PMID: 34210283 PMCID: PMC8247102 DOI: 10.1186/s12882-021-02437-4] [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: 03/25/2021] [Accepted: 06/03/2021] [Indexed: 11/13/2022] Open
Abstract
Background Minimal change disease is a common cause of nephrotic syndrome in adults. Higher relapse rate put patients at risk of steroids toxicity due to long-term exposure. Rituximab has been suggested to maintain long time remission and withdraw steroids and other immunosuppressants with fewer adverse events. However, optimal dose and dosing interval have not been explored. Methods Twenty-five patients were enrolled from 2017-10 to 2020-03 in Nanfang Hospital in China. Clinical and biological data were extracted from medical records and laboratory databases. Therapy composed of 375mg/m2 rituximab once three weeks for 3 dose and corticosteroid was applied. Complete remission was defined as reduction of proteinuria to 0.3g/d. Remission rate, relapse rate, steroids used before and after rituximab therapy and adverse effects were documented at a mean time of 14.71 months. Results Twenty-two patients achieved complete remission for an average of 3.26 months and only 3 patients experienced one relapse respectively during the follow-up period. The mean remission maintenance time was 11.6 months, and was 5 months after steroids withdrawal. Steroids dose at last follow-up was 6.09mg/d, which was significantly reduced compared to 28.15mg/d before rituximab. Relapse rate before and after rituximab was 1.43 and 0.1, respectively. Only four minor adverse events were recorded. Conclusions Therapy consisted of 375mg/m2 rituximab once three weeks for 3 dose combined with corticosteroid is effective in inducing remission in adult patients with minimal change disease. Both of the relapse rate and dose of steroids used are significantly decreased with fewer side effects. Supplementary Information The online version contains supplementary material available at 10.1186/s12882-021-02437-4.
Collapse
Affiliation(s)
- Diankun Liu
- National Clinical Research Center for Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhanmei Zhou
- National Clinical Research Center for Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Mengyi Wang
- National Clinical Research Center for Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Sheng Nie
- National Clinical Research Center for Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jun Li
- National Clinical Research Center for Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bianxiang Hu
- National Clinical Research Center for Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wenjuan He
- National Clinical Research Center for Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Guobao Wang
- National Clinical Research Center for Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China. .,Renal Division, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510515, China.
| | - Jun Ai
- National Clinical Research Center for Kidney Disease, Guangdong Provincial Clinical Research Center for Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China. .,Renal Division, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510515, China.
| |
Collapse
|
21
|
Pérez-Sáez MJ, Uffing A, Leon J, Murakami N, Watanabe A, Borges TJ, Sabbisetti VS, Cureton P, Kenyon V, Keating L, Yee K, Fernandes Satiro CA, Serena G, Hildebrandt F, Riella CV, Libermann TA, Wang M, Pascual J, Bonventre JV, Cravedil P, Fasano A, Riella LV. Immunological Impact of a Gluten-Free Dairy-Free Diet in Children With Kidney Disease: A Feasibility Study. Front Immunol 2021; 12:624821. [PMID: 34149688 PMCID: PMC8208082 DOI: 10.3389/fimmu.2021.624821] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 05/04/2021] [Indexed: 12/20/2022] Open
Abstract
Kidney disease affects 10% of the world population and is associated with increased mortality. Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children, often failing standard immunosuppression. Here, we report the results of a prospective study to investigate the immunological impact and safety of a gluten-free and dairy-free (GF/DF) diet in children with SRNS. The study was organized as a four-week summer camp implementing a strict GF/DF diet with prospective collection of blood, urine and stool in addition to whole exome sequencing WES of DNA of participants. Using flow cytometry, proteomic assays and microbiome metagenomics, we show that GF/DF diet had a major anti-inflammatory effect in all participants both at the protein and cellular level with 4-fold increase in T regulatory/T helper 17 cells ratio and the promotion of a favorable regulatory gut microbiota. Overall, GF/DF can have a significant anti-inflammatory effect in children with SRNS and further trials are warranted to investigate this potential dietary intervention in children with SRNS.
Collapse
Affiliation(s)
- María José Pérez-Sáez
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, United States.,Servicio de Nefrología, Hospital del Mar, Barcelona, Spain
| | - Audrey Uffing
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Juliette Leon
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Naoka Murakami
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Andreia Watanabe
- Department of Pediatrics, Pediatric Nephrology Unit, Instituto da Criança, Hospital das Clínicas - University of São Paulo Medical School (USP), São Paulo, Brazil
| | - Thiago J Borges
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, United States.,Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, United States
| | - Venkata S Sabbisetti
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Pamela Cureton
- Center for Celiac Research and Treatment, Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA, United States
| | - Victoria Kenyon
- Center for Celiac Research and Treatment, Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA, United States
| | - Leigh Keating
- Experimental Therapeutics/Interventional Trials Center, Boston Children's Hospital, Boston, MA, United States
| | - Karen Yee
- Center for Clinical Investigation, Brigham & Women's Hospital, Boston, MA, United States
| | - Carla Aline Fernandes Satiro
- Division of Nutrition, Instituto da Criança, Hospital das Clínicas - University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Gloria Serena
- Center for Celiac Research and Treatment, Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA, United States
| | - Friedhelm Hildebrandt
- Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
| | - Cristian V Riella
- Renal Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Towia A Libermann
- Beth Israel Deaconess Medical Center Genomics, Proteomics, Bioinformatics and Systems Biology Center, Division of Interdisciplinary Medicine and Biotechnology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Minxian Wang
- Medical and Population Genetics Program, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
| | - Julio Pascual
- Servicio de Nefrología, Hospital del Mar, Barcelona, Spain
| | - Joseph V Bonventre
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Paolo Cravedil
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Alessio Fasano
- Center for Celiac Research and Treatment, Massachusetts General Hospital for Children, Harvard Medical School, Boston, MA, United States
| | - Leonardo V Riella
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, United States.,Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, United States.,Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| |
Collapse
|
22
|
Guzmán Morais B, Ordóñez Álvarez FÁ, Santos Rodríguez F, Martín Ramos S, Fernández Novo G. [Rituximab treatment in pediatric patients with steroid-dependent nephrotic syndrome: a tertiary hospital]. An Pediatr (Barc) 2021; 96:S1695-4033(20)30529-4. [PMID: 33518484 DOI: 10.1016/j.anpedi.2020.12.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 11/30/2020] [Accepted: 12/09/2020] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Corticosteroids have had a central role in the treatment of nephrotic syndrome. The management of these patients who become dependent to steroids is complex, involving different immunosuppressive drugs patterns. The monoclonal antibody anti CD20, Rituximab, is likely to have beneficial effects in cases of steroid-dependent nephrotic syndrome patients with no easy resolution, even when we cannot make a statement about the specific role in the impact. We bring our personal experience in pediatric patients treated with this medication during the last years, to provide a thorough overview and useful information about the role of Rituximab in this pathology. METHODS Retrospective study in patients with steroid-dependent idiopathic nephrotic syndrome controlled in the division of Pediatric Nephrology of a spanish tertiary hospital in those patients who had received at least one treatment cycle of Rituximab, at any moment along the evolution of the disease. RESULTS The study involved 8 patients. All of them previously received immunosuppressive therapy. The Rituximab were administered as an intravenous infusion, in a dose of 375 mg/m2, and all doses were administered in a period during which the disease was in remission. The depletion of lymphocytes B (CD 19%) were confirmed after the first dose of Rituximab except for one, with a lymphocyte count of 1%. The period of depletion lasts 10.3 months (median; range 6.5-16 months), and only one of the patients registered a relapse of the disease in this period. A reduction of relapses suffered by patients has been shown after the treatment began (3.6 relapses/year in the previous year to the start of the treatment vs. 0.1 relapses/year during the first year post-rituximab). The relapse-free survival in the first year reached 83.3% in patients who suffered more than one relapse (75% of patients), and without a relapse after the treatment began in 2 cases. One or more drugs could be removed in 87.5% of patients after the first cycle of rituximab. After the rituximab treatment, we reached a 96.5% decrease in the corticosteroids doses administered (28.5 mg/m2/day during the 3 months pre-treatment vs. 1 mg/m2/day in the last 3 months of patient monitoring). Not a significant observed adverse effect attributed to the drug after the post-rituximab monitoring period (median 46.5 months, range 5-97 months). CONCLUSION The favorable results reported after rituximab treatment in our patients seems to confirm the effectiveness of this drug in the steroid-dependent nephrotic syndrome, making that therapeutic option into consideration and legitimating the use of the drug in complex cases involving pediatric patients. Even so, it seems recommendable to design pertinent studies to clarify, among others, the optimum regimen of the treatment (dose, interval and cycles), clinical repercussion and potential adverse effects in long terms.
Collapse
Affiliation(s)
- Beatriz Guzmán Morais
- Servicio de Pediatría, Hospital Clínico Universitario de Valencia, Valencia, España.
| | | | - Fernando Santos Rodríguez
- Servicio de Nefrología Infantil, Hospital Universitario Central de Asturias, Oviedo, Asturias, España
| | - Silvia Martín Ramos
- Servicio de Nefrología Infantil, Hospital Universitario Central de Asturias, Oviedo, Asturias, España
| | - Gema Fernández Novo
- Servicio de Nefrología Infantil, Hospital Universitario Central de Asturias, Oviedo, Asturias, España
| |
Collapse
|
23
|
CD80 Insights as Therapeutic Target in the Current and Future Treatment Options of Frequent-Relapse Minimal Change Disease. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6671552. [PMID: 33506028 PMCID: PMC7806396 DOI: 10.1155/2021/6671552] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 12/26/2020] [Indexed: 12/14/2022]
Abstract
Minimal change disease (MCD) is the most common cause of idiopathic nephrotic syndrome in children, and it is well known for its multifactorial causes which are the manifestation of the disease. Proteinuria is an early consequence of podocyte injury and a typical sign of kidney disease. Steroid-sensitive patients react well with glucocorticoids, but there is a high chance of multiple relapses. CD80, also known as B7-1, is generally expressed on antigen-presenting cells (APCs) in steroid-sensitive MCD patients. Various glomerular disease models associated with proteinuria demonstrated that the detection of CD80 with the increase of urinary CD80 was strongly associated closely with frequent-relapse MCD patients. The role of CD80 in MCD became controversial because one contradicts finding. This review covers the treatment alternatives for MCD with the insight of CD80 as a potential therapeutic target. The promising effectiveness of CD20 (rituximab) antibody and CD80 inhibitor (abatacept) encourages further investigation of CD80 as a therapeutic target in frequent-relapse MCD patients. Therapeutic-based antibody towards CD80 (galiximab) had never been investigated in MCD or any kidney-related disease; hence, the role of CD80 is still undetermined. A new therapeutic approach towards MCD is essential to provide broader effective treatment options besides the general immunosuppressive agents with gruesome adverse effects.
Collapse
|
24
|
Podestà MA, Ponticelli C. Autoimmunity in Focal Segmental Glomerulosclerosis: A Long-Standing Yet Elusive Association. Front Med (Lausanne) 2020; 7:604961. [PMID: 33330569 PMCID: PMC7715033 DOI: 10.3389/fmed.2020.604961] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 10/26/2020] [Indexed: 01/17/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a histological term that describes a pathologic renal entity affecting both adults and children, with a wide array of possible underlying etiologies. Podocyte damage with scarring, the hallmark of this condition, leads to altered permeability of the glomerular barrier, which may result in massive proteinuria and relentless renal function deterioration. A definite cause of focal segmental glomerulosclerosis can be confirmed in a minority of cases, while most forms have been traditionally labeled as primary or idiopathic. Despite this definition, increasing evidence indicates that primary forms are a heterogenous group rather than a single disease entity: several circulating factors that may affect glomerular permeability have been proposed as potential culprits, and both humoral and cellular immunity have been implicated in the pathogenesis of the disease. Consistently, immunosuppressive drugs are considered as the cornerstone of treatment for primary focal segmental glomerulosclerosis, but response to these agents and long-term outcomes are highly variable. In this review we provide a summary of historical and recent advances on the pathogenesis of primary focal segmental glomerulosclerosis, focusing on implications for its differential diagnosis and treatment.
Collapse
|
25
|
Padala SA, Birkelo B, Mohammed A, Kapoor R, Mulloy L, Rawla P. Collapsing focal segmental sclerosis in an HIV-negative patient. Clin Case Rep 2020; 8:2166-2171. [PMID: 33235752 PMCID: PMC7669430 DOI: 10.1002/ccr3.3078] [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] [Received: 02/25/2020] [Revised: 04/21/2020] [Accepted: 06/06/2020] [Indexed: 01/10/2023] Open
Abstract
Collapsing focal segmental glomerulosclerosis (FSGS) is classically seen in HIV-infected patients and carries a dismal prognosis. It can also occur in HIV-negative patients in which case, early aggressive treatment with glucocorticoids may be helpful with improvement in both proteinuria and renal function.
Collapse
Affiliation(s)
- Sandeep Anand Padala
- Department of Medicine, NephrologyMedical College of GeorgiaAugusta UniversityAugustaGAUSA
| | - Bethany Birkelo
- Department of MedicineMedical College of GeorgiaAugusta UniversityAugustaGAUSA
| | - Azeem Mohammed
- Department of Medicine, NephrologyMedical College of GeorgiaAugusta UniversityAugustaGAUSA
| | - Rajan Kapoor
- Department of Medicine, NephrologyMedical College of GeorgiaAugusta UniversityAugustaGAUSA
| | - Laura Mulloy
- Department of Medicine, NephrologyMedical College of GeorgiaAugusta UniversityAugustaGAUSA
| | - Prashanth Rawla
- Department of Internal MedicineSovah HealthMartinsvilleVAUSA
| |
Collapse
|
26
|
Nishizono R, Kogou H, Ishizaki Y, Minakawa A, Kikuchi M, Inagaki H, Sato Y, Fujimoto S. Concurrent minimal change nephrotic syndrome and type 1 diabetes mellitus in an adult Japanese woman: a case report. BMC Nephrol 2020; 21:410. [PMID: 32967631 PMCID: PMC7510261 DOI: 10.1186/s12882-020-02071-6] [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] [Received: 04/19/2020] [Accepted: 09/15/2020] [Indexed: 01/04/2023] Open
Abstract
Background Concurrent type 1 diabetes mellitus (T1DM) and idiopathic nephrotic syndrome is rare, and most previously reported cases were in children. We report the case of an adult woman who developed T1DM and minimal change nephrotic syndrome (MCNS) nearly simultaneously. Case presentation A 24-year-old woman had first presented to another hospital with nausea, vomiting, and fatigue. She was diagnosed with diabetic ketoacidosis and T1DM on the basis of her hyperglycemia, ketoacidosis, and positive anti-glutamic acid decarboxylase antibody test result. Rapid infusion of normal saline and insulin administration alleviated hyperglycemia and ketoacidosis. Two weeks after admission, however, she developed nephrotic syndrome (NS) with rapidly decreasing urine volume. She was referred to our hospital with a diagnosis of acute kidney injury. Although she temporarily required dialysis and high doses of insulin, within 1 month NS and acute kidney injury had been alleviated by oral prednisolone and low-density lipoprotein apheresis. Renal biopsy showed minor glomerular abnormalities without diabetic nephropathy, so we diagnosed her with MCNS. Seven weeks after the discharge, NS relapsed, and cyclosporine was added to prednisolone. However, NS relapsed twice within the next 4 months, so we started her on rituximab. At 6 months after initiating rituximab therapy, she remained in complete remission. Her mother also had T1DM but not MCNS. The patient had HLA-DRB1*09:01/09:01, DQB1*03:03/03:03, and her mother had HLA-DRB1*04:05/09:01, DQB1*03:03/04:01. Conclusions Concurrent T1DM and MCNS is rare and their coexistence might be coincidental. Alternatively, they might have been caused by an underlying, unidentified genetic predisposition. Previous reports and our patient’s findings suggest that specific HLA alleles and haplotypes or a Th1/Th2 imbalance might be associated with T1DM and MCNS that occurred nearly simultaneously.
Collapse
Affiliation(s)
- Ryuzoh Nishizono
- Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
| | - Hiroki Kogou
- Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Yuri Ishizaki
- Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Akihiro Minakawa
- Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Masao Kikuchi
- Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Hiroko Inagaki
- Dialysis Division, University of Miyazaki Hospital, Miyazaki, Japan
| | - Yuji Sato
- Department of Nephrology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.,Dialysis Division, University of Miyazaki Hospital, Miyazaki, Japan
| | - Shouichi Fujimoto
- Dialysis Division, University of Miyazaki Hospital, Miyazaki, Japan.,Department of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| |
Collapse
|
27
|
Candelier JJ, Lorenzo HK. Idiopathic nephrotic syndrome and serum permeability factors: a molecular jigsaw puzzle. Cell Tissue Res 2019; 379:231-243. [PMID: 31848752 DOI: 10.1007/s00441-019-03147-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/19/2019] [Indexed: 12/14/2022]
Abstract
Nephrotic syndrome is traditionally defined using the triad of edema, hypoalbuminemia, and proteinuria, but this syndrome is very heterogeneous and difficult to clarify. Its idiopathic form (INS) is probably the most harmful and essentially comprises two entities: minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). We will consider some hypotheses regarding the mechanisms underlying INS: (i) the presence of several glomerular permeability factors in the sera of patients that alter the morphology and function of podocytes leading to proteinuria, (ii) the putative role of immune cells. Thanks to recent data, our understanding of these disorders is evolving towards a more multifactorial origin. In this context, circulating factors may be associated according to sequential kinetic mechanisms or micro-environmental changes that need to be determined. In addition, the resulting proteinuria may trigger more proteinuria enhancing the glomerular destabilization.
Collapse
Affiliation(s)
- Jean-Jacques Candelier
- INSERM U1197, Hôpital Paul Brousse, 14 Avenue Paul Vaillant Couturier, 94800, Villejuif, France.,Université Paris-Saclay, Campus Universitaire d'Orsay, 91405, Orsay, France
| | - Hans-Kristian Lorenzo
- INSERM U1197, Hôpital Paul Brousse, 14 Avenue Paul Vaillant Couturier, 94800, Villejuif, France. .,Université Paris-Saclay, Campus Universitaire d'Orsay, 91405, Orsay, France. .,Service de Néphrologie, Hôpital Bicêtre, Faculté de Médecine Paris-Saclay, 94270, Le Kremlin-Bicêtre, France.
| |
Collapse
|
28
|
Benabdellah N, Izzedine H, Bentata Y, Haddiya I. Ovarian tumor and glomerulopathies: case report and review of the literature. Pan Afr Med J 2019; 34:75. [PMID: 31819791 PMCID: PMC6884736 DOI: 10.11604/pamj.2019.34.75.6008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 07/15/2019] [Indexed: 11/11/2022] Open
Abstract
We describe a patient who developed nephrotic syndrome in the setting of ovarian tumor. A kidney biopsy showed minimal change nephropathy (MCN). CT scan and MR imaging followed by surgery lead to diagnostic of ovarian dermoid cyst. Surgery combined with corticosteroids resulted in a complete remission of nephrotic syndrome with disappearance of proteinuria after 3 weeks. Ten other cases of ovarian tumor associated with glomerulopathy are reviewed. This is the second case of an ovarian teratoma associated with MCN. Accurate history, physical examination, laboratory data, and kidney biopsy are highlighted in establishing the correct diagnosis in such patients.
Collapse
Affiliation(s)
- Nawal Benabdellah
- Department of Nephrology, University Hospital Mohamed VI, Oujda, Morocco
| | - Hassan Izzedine
- Department of Nephrology, Pitie-Salpetiere Hospital, 43 Boulevard de l'Hôpital, 75013 Paris, France
| | - Yassamine Bentata
- Department of Nephrology, University Hospital Mohamed VI, Oujda, Morocco
| | - Intissar Haddiya
- Department of Nephrology, University Hospital Mohamed VI, Oujda, Morocco
| |
Collapse
|
29
|
Cytotoxic T- Lymphocyte Antigen-4 (CTLA4) Gene Expression and Urinary CTLA4 Levels in Idiopathic Nephrotic Syndrome. Indian J Pediatr 2019; 86:26-31. [PMID: 29968132 DOI: 10.1007/s12098-018-2734-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 06/08/2018] [Indexed: 11/27/2022]
Abstract
OBJECTIVES To detect Cytotoxic T- Lymphocyte Antigen-4 (CTLA4) single nucleotide polymorphisms (SNPs) at +49A/G (rs231775) and -318C/T (rs5742909) positions in children with idiopathic nephrotic syndrome (INS) and also assay urinary soluble CTLA4 (sCTLA4) levels in children with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and steroid sensitive nephrotic syndrome (SSNS) in remission. METHODS The study included 59 patients of INS (MCD-23, FSGS-15 and SSNS in remission-21) and 35 healthy controls. The CTLA4 SNPs profiling was done in peripheral blood mononuclear cells and urinary sCTLA4 level was assayed by ELISA kit. RESULTS Although frequency of homozygous +49 GG (rs4553808) genotype (26.3% vs. 11.4%; p = 0.231) and G allele (52.6% vs. 40%; p = 0.216) were found to be higher in INS as compared to controls, the differences were statistically non-significant. Genotypes GG, AG, AA and alleles A and G frequencies were comparable among MCD, FSGS and controls. SNP at -318 C/T (rs5742909) did not show homozygous TT genotype both in INS as well as controls. Median urinary sCTLA4/creatinine level was significantly higher in MCD as compared to FSGS (p = 0.027), SSNS in remission (p = 0.001) and controls (p = 0.003). CONCLUSIONS The positive associations of +49 GG genotype and G allele in patients with nephrotic syndrome were not observed. The frequencies did not differ significantly among MCD, FSGS and controls. Urinary sCTLA4 level was significantly increased in MCD; suggesting its possible role in the pathogenesis of disease.
Collapse
|
30
|
Cortazar FB, Rosenthal J, Laliberte K, Niles JL. Continuous B-cell depletion in frequently relapsing, steroid-dependent and steroid-resistant nephrotic syndrome. Clin Kidney J 2018; 12:224-231. [PMID: 30976400 PMCID: PMC6452201 DOI: 10.1093/ckj/sfy067] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Indexed: 12/21/2022] Open
Abstract
Background Patients with frequently relapsing (FR), steroid-dependent (SD) and steroid-resistant (SR) nephrotic syndrome are a therapeutic challenge with limited treatment options. Here, we retrospectively analyze the efficacy and safety of rituximab-induced continuous B-cell depletion in these populations. Methods Patients were included if they were at least 18 years of age and had FR, SD or SR minimal change disease (MCD) or primary focal segmental glomerulosclerosis (FSGS) and were treated with a strategy of continuous B-cell depletion. Partial remission (PR) was defined as a urinary protein:creatinine ratio (UPCR) of ≤3.5 g/g and a 50% reduction in the UPCR from baseline. Complete remission (CR) was defined as a UPCR ≤0.3 g/g. Results We identified 20 patients with MCD (n = 13) or FSGS (n = 7) who fulfilled the inclusion criteria. All patients had either SD (n = 12), SR (n = 7) or FR (n = 1) disease. Patients received a median of nine rituximab doses [interquartile range (IQR) 7.5, 11] and were treated for a median time of 28 months (IQR 23, 41). Prednisone was weaned from a median of 60 mg daily (IQR 40, 60) at rituximab initiation to 4.5 mg daily (IQR 0, 5.5) by 12 months. All patients achieved PR. CR occurred in 11 of 13 patients with FR or SD disease, but only 1 of 7 patients with SR disease (logrank P = 0.01). Four relapses occurred, all in patients with SR disease. Three serious infections occurred over 70.3 patient-years. Conclusion Continuous B-cell depletion is a therapeutic option in the management of complicated nephrotic syndrome. Additional studies are needed to clarify the utility of this strategy.
Collapse
Affiliation(s)
- Frank B Cortazar
- Vasculitis and Glomerulonephritis Center, Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA
| | - Jillian Rosenthal
- Vasculitis and Glomerulonephritis Center, Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA
| | - Karen Laliberte
- Vasculitis and Glomerulonephritis Center, Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA
| | - John L Niles
- Vasculitis and Glomerulonephritis Center, Division of Nephrology, Massachusetts General Hospital, Boston, MA, USA
| |
Collapse
|
31
|
Bertelli R, Bonanni A, Caridi G, Canepa A, Ghiggeri GM. Molecular and Cellular Mechanisms for Proteinuria in Minimal Change Disease. Front Med (Lausanne) 2018; 5:170. [PMID: 29942802 PMCID: PMC6004767 DOI: 10.3389/fmed.2018.00170] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 05/15/2018] [Indexed: 12/15/2022] Open
Abstract
Minimal Change Disease (MCD) is a clinical condition characterized by acute nephrotic syndrome, no evident renal lesions at histology and good response to steroids. However, frequent recurrence of the disease requires additional therapies associated with steroids. Such multi-drug dependence and frequent relapses may cause disease evolution to focal and segmental glomerulosclerosis (FSGS) over time. The differences between the two conditions are not well defined, since molecular mechanisms may be shared by the two diseases. In some cases, genetic analysis can make it possible to distinguish MCD from FSGS; however, there are cases of overlap. Several hypotheses on mechanisms underlying MCD and potential molecular triggers have been proposed. Most studies were conducted on animal models of proteinuria that partially mimic MCD and may be useful to study glomerulosclerosis evolution; however, they do not demonstrate a clear-cut separation between MCD and FSGS. Puromycin Aminonucleoside and Adriamycin nephrosis are models of glomerular oxidative damage, characterized by loss of glomerular basement membrane polyanions resembling MCD at the onset and, at more advanced stages, by glomerulosclerosis resembling FSGS. Also Buffalo/Mna rats present initial lesions of MCD, subsequently evolving to FSGS; this mechanism of renal damage is clearer since this rat strain inherits the unique characteristic of overexpressing Th2 cytokines. In Lipopolysaccharide nephropathy, an immunological condition of renal toxicity linked to B7-1(CD80), mice develop transient proteinuria that lasts a few days. Overall, animal models are useful and necessary considering that they reproduce the evolution from MCD to FSGS that is, in part, due to persistence of proteinuria. The role of T/Treg/Bcells on human MCD has been discussed. Many cytokines, immunomodulatory mechanisms, and several molecules have been defined as a specific cause of proteinuria. However, the hypothesis of a single cell subset or molecule as cause of MCD is not supported by research and an interactive process seems more logical. The implication or interactive role of oxidants, Th2 cytokines, Th17, Tregs, B7-1(CD80), CD40/CD40L, c-Mip, TNF, uPA/suPAR, Angiopoietin-like 4 still awaits a definitive confirmation. Whole genome sequencing studies could help to define specific genetic features that justify a definition of MCD as a “clinical-pathology-genetic entity.”
Collapse
Affiliation(s)
| | | | | | - Alberto Canepa
- Nephrology, Dialysis, Transplantation Unit, Integrated Department of Pediatrics and Hemato-Oncology Sciences, Istituto Giannina Gaslini IRCCS, Genoa, Italy
| | - G M Ghiggeri
- Laboratory of Molecular Nephrology, Genoa, Italy.,Nephrology, Dialysis, Transplantation Unit, Integrated Department of Pediatrics and Hemato-Oncology Sciences, Istituto Giannina Gaslini IRCCS, Genoa, Italy
| |
Collapse
|
32
|
Kofman T, Oniszczuk J, Lang P, Grimbert P, Audard V. [Current insights about recurrence of glomerular diseases after renal transplantation]. Nephrol Ther 2018; 14:179-188. [PMID: 29706414 DOI: 10.1016/j.nephro.2018.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Recurrence of glomerular disease after renal transplantation is a frequent cause of graft loss. Incidence, risk factors and outcome of recurrence are widely due to the underlying glomerular disease. Graft biopsy analysis is required to confirm the definitive diagnosis of recurrence and to start an appropriate therapy that, in some cases, remains challenging to prevent graft failure. Increased use of protocol biopsy and recent advances in our understanding of the pathogenesis of some glomerular diseases with the identification of some relevant biomarkers provide a unique opportunity to initiate kidney-protective therapy at early stages of recurrence on the graft. This review summarizes our current knowledge on the management of many recurrent primary and secondary glomerulonephritis after kidney transplantation.
Collapse
Affiliation(s)
- Tomek Kofman
- Service de néphrologie et transplantation, hôpital Henri-Mondor, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France; Institut francilien de recherche en néphrologie et transplantation (IFRNT), université Paris Est-Créteil (Upec), avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France
| | - Julie Oniszczuk
- Service de néphrologie et transplantation, hôpital Henri-Mondor, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France; Institut francilien de recherche en néphrologie et transplantation (IFRNT), université Paris Est-Créteil (Upec), avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France
| | - Philippe Lang
- Service de néphrologie et transplantation, hôpital Henri-Mondor, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France; Institut francilien de recherche en néphrologie et transplantation (IFRNT), université Paris Est-Créteil (Upec), avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France
| | - Philippe Grimbert
- Service de néphrologie et transplantation, hôpital Henri-Mondor, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France; Institut francilien de recherche en néphrologie et transplantation (IFRNT), université Paris Est-Créteil (Upec), avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France
| | - Vincent Audard
- Service de néphrologie et transplantation, hôpital Henri-Mondor, avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France; Institut francilien de recherche en néphrologie et transplantation (IFRNT), université Paris Est-Créteil (Upec), avenue du Maréchal-de-Lattre-de-Tassigny, 94010 Créteil cedex, France.
| |
Collapse
|
33
|
Effect of Combined Gluten-Free, Dairy-Free Diet in Children With Steroid-Resistant Nephrotic Syndrome: An Open Pilot Trial. Kidney Int Rep 2018; 3:851-860. [PMID: 30116795 PMCID: PMC6093178 DOI: 10.1016/j.ekir.2018.02.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 02/11/2018] [Accepted: 02/26/2018] [Indexed: 11/24/2022] Open
Abstract
Introduction Steroid-resistant nephrotic syndrome (SRNS) affects both children and adults and has a high rate of progression to end-stage renal disease. Although a subset of patients have well-characterized genetic mutation(s), in the majority of cases, the etiology is unknown. Over the past 50 years, a number of case reports have suggested the potential impact of dietary changes in controlling primary nephrotic syndrome, especially gluten and dairy restrictions. Methods We have designed a prospective, open-label, nonrandomized, pilot clinical trial, to study the effect of a gluten-free and dairy-free (GF/DF) diet in children with SRNS. The study will be organized as a 4-week summer camp to implement a GF/DF diet in a tightly controlled and monitored setting. Blood, urine, and stool samples will be collected at different time points during the study. Results The primary end point is a reduction of more than 50% in the urine protein:creatinine ratio. The secondary end points include changes in urine protein, kidney function, and serum albumin, as well as effects in immune activation, kidney injury biomarkers, and gut microbiome composition and function (metagenomic/metatranscriptomic). Conclusion This study will advance the field by testing the effect of dietary changes in patients with SRNS in a highly controlled camp environment. In addition, we hope the results will help to identify a responder profile that may guide the design of a larger trial for further investigation.
Collapse
|
34
|
Dorval G, Gribouval O, Martinez-Barquero V, Machuca E, Tête MJ, Baudouin V, Benoit S, Chabchoub I, Champion G, Chauveau D, Chehade H, Chouchane C, Cloarec S, Cochat P, Dahan K, Dantal J, Delmas Y, Deschênes G, Dolhem P, Durand D, Ekinci Z, El Karoui K, Fischbach M, Grunfeld JP, Guigonis V, Hachicha M, Hogan J, Hourmant M, Hummel A, Kamar N, Krummel T, Lacombe D, Llanas B, Mesnard L, Mohsin N, Niaudet P, Nivet H, Parvex P, Pietrement C, de Pontual L, Noble CP, Ribes D, Ronco P, Rondeau E, Sallee M, Tsimaratos M, Ulinski T, Salomon R, Antignac C, Boyer O. Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome. Pediatr Nephrol 2018; 33:473-483. [PMID: 29058154 DOI: 10.1007/s00467-017-3819-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Revised: 09/05/2017] [Accepted: 09/07/2017] [Indexed: 10/18/2022]
Abstract
BACKGROUND Familial steroid-sensitive nephrotic syndrome (SSNS) is a rare condition. The disease pathophysiology remains elusive. However, bi-allelic mutations in the EMP2 gene were identified, and specific variations in HLA-DQA1 were linked to a high risk of developing the disease. METHODS Clinical data were analyzed in 59 SSNS families. EMP2 gene was sequenced in families with a potential autosomal recessive (AR) inheritance. Exome sequencing was performed in a subset of 13 families with potential AR inheritance. Two variations in HLA-DQA1 were genotyped in the whole cohort. RESULTS Transmission was compatible with an AR (n = 33) or autosomal dominant (AD, n = 26) inheritance, assuming that familial SSNS is a monogenic trait. Clinical features did not differ between AR and AD groups. All patients, including primary (n = 7) and secondary steroid resistant nephrotic syndrone (SRNS), (n = 13) were sensitive to additional immunosuppressive therapy. Both HLA-DQA1 variations were found to be highly linked to the disease (OR = 4.34 and OR = 4.89; p < 0.001). Exome sequencing did not reveal any pathogenic mutation, neither did EMP2 sequencing. CONCLUSIONS Taken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the HLA-DQA1 variation enrichments suggest a complex mode of inheritance.
Collapse
Affiliation(s)
- Guillaume Dorval
- INSERM UMR1163, Laboratory of Hereditary Kidney Diseases, Imagine Institute, 24 Boulevard du Montparnasse, 75015, Paris, France. .,Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
| | - Olivier Gribouval
- INSERM UMR1163, Laboratory of Hereditary Kidney Diseases, Imagine Institute, 24 Boulevard du Montparnasse, 75015, Paris, France.,Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France
| | - Vanesa Martinez-Barquero
- INSERM UMR1163, Laboratory of Hereditary Kidney Diseases, Imagine Institute, 24 Boulevard du Montparnasse, 75015, Paris, France.,Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France
| | - Eduardo Machuca
- INSERM UMR1163, Laboratory of Hereditary Kidney Diseases, Imagine Institute, 24 Boulevard du Montparnasse, 75015, Paris, France
| | - Marie-Josèphe Tête
- INSERM UMR1163, Laboratory of Hereditary Kidney Diseases, Imagine Institute, 24 Boulevard du Montparnasse, 75015, Paris, France.,Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France
| | - Véronique Baudouin
- Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Paris, France
| | - Stéphane Benoit
- Department of Nephrology, University Hospital of Tours, Tours, France
| | - Imen Chabchoub
- Department of Pediatrics, Sfax University, Sfax, Tunisia
| | - Gérard Champion
- Department of Pediatrics, University Hospital of Angers, Angers, France
| | - Dominique Chauveau
- Department of Nephrology and Organ Transplantation, University Hospital Rangueil, Toulouse, France
| | - Hassib Chehade
- Department of Pediatrics, Division of Pediatric Nephrology, Lausanne University Hospital, Lausanne, Switzerland
| | - Chokri Chouchane
- Department of Pediatrics, Monastir University, Monastir, Tunisia
| | - Sylvie Cloarec
- Department of Nephrology, University Hospital of Tours, Tours, France
| | - Pierre Cochat
- Department of Pediatric Nephrology, Claude-Bernard Lyon 1 University, Bron, France
| | - Karin Dahan
- Department of Human Genetics, Institute of Pathology and Genetics, Gosselies, Belgium
| | - Jacques Dantal
- Nephrology and Immunology Department, University Hospital of Nantes, Nantes, France
| | - Yahsou Delmas
- Department of Nephrology, University Hospital of Bordeaux, Bordeaux, France
| | - Georges Deschênes
- Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris, Robert Debré Hospital, Paris, France
| | - Phillippe Dolhem
- Department of Pediatrics, Saint-Quentin Hospital, Saint-Quentin, France
| | - Dominique Durand
- Department of Nephrology and Organ Transplantation, University Hospital Rangueil, Toulouse, France
| | | | - Khalil El Karoui
- Department of Nephrology, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Hospital, Paris, France
| | - Michel Fischbach
- Nephrology Dialysis Transplantation Children's Unit, University Hospital Hautepierre, Strasbourg, France
| | - Jean-Pierre Grunfeld
- Department of Nephrology, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Hospital, Paris, France
| | - Vincent Guigonis
- Department of Pediatrics, University Hospital of Limoges, Limoges, France
| | | | - Julien Hogan
- Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris, Armand Trousseau Hospital, Paris, France
| | - Maryvonne Hourmant
- Nephrology and Immunology Department, University Hospital of Nantes, Nantes, France
| | - Aurélie Hummel
- Department of Nephrology, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Hospital, Paris, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, University Hospital Rangueil, Toulouse, France
| | - Thierry Krummel
- Department of Nephrology, University Hospital Hautepierre, Strasbourg, France
| | - Didier Lacombe
- Department of Genetics, University Hospital of Bordeaux, Bordeaux, France
| | - Brigitte Llanas
- Department of Pediatrics, University Hospital of Bordeaux, Bordeaux, France
| | - Laurent Mesnard
- Department of Nephrology and Dialysis, Assistance Publique-Hôpitaux de Paris, Tenon Hospital, Paris, France.,Sorbonne University, UPMC University Paris 06, Paris, France.,INSERM, UMR_S 1155, 75020, Paris, France
| | - Nabil Mohsin
- College of Medicine, Sultan Qaboos University, Muscat, Oman
| | - Patrick Niaudet
- Department of Pediatric Nephrology, Centre de référence du syndrome néphrotique idiopathique de l'enfant et l'adulte, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Hospital, Paris, France.,Centre de Référence Syndrome Néphrotique Idiopathique de l'enfant et de l'adulte, Paris, France
| | - Hubert Nivet
- Department of Nephrology, University Hospital of Tours, Tours, France
| | - Paloma Parvex
- Department of Pediatrics, Division of Pediatric Nephrology, Geneva University Hospital, Geneva, Switzerland
| | - Christine Pietrement
- Departement of Pediatrics, Nephrology Unit, University Hospital of Reims, Reims, France.,Faculty of Medicine, Laboratory of Biochemistry and Molecular Biology, UMR, CNRS/URCA n°7369, University of Champagne-Ardenne, Reims, France
| | - Loic de Pontual
- Department of Pediatrics, Assistance Publique-Hôpitaux de Paris, Jean Verdier Hospital, Bondy, France
| | - Claire Pouteil Noble
- Department of Nephrology and Transplantation, University Hospital of Lyon, Lyon, France
| | - David Ribes
- Department of Nephrology and Organ Transplantation, University Hospital Rangueil, Toulouse, France
| | - Pierre Ronco
- Department of Nephrology and Dialysis, Assistance Publique-Hôpitaux de Paris, Tenon Hospital, Paris, France.,Sorbonne University, UPMC University Paris 06, Paris, France.,INSERM, UMR_S 1155, 75020, Paris, France
| | - Eric Rondeau
- Department of Nephrology and Dialysis, Assistance Publique-Hôpitaux de Paris, Tenon Hospital, Paris, France
| | - Marion Sallee
- Department of Nephrology and Kidney Transplantation, The Conception Hospital, Marseille, France
| | - Michel Tsimaratos
- Department of Multidisciplinary Pediatrics Timone, Assistance Publique Hôpitaux de Marseille, Aix-Marseille University, Marseille, France
| | - Tim Ulinski
- Department of Pediatric Nephrology, Assistance Publique-Hôpitaux de Paris, Armand Trousseau Hospital, Paris, France
| | - Rémi Salomon
- INSERM UMR1163, Laboratory of Hereditary Kidney Diseases, Imagine Institute, 24 Boulevard du Montparnasse, 75015, Paris, France.,Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.,Department of Pediatric Nephrology, Centre de référence du syndrome néphrotique idiopathique de l'enfant et l'adulte, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Hospital, Paris, France.,Centre de Référence Syndrome Néphrotique Idiopathique de l'enfant et de l'adulte, Paris, France
| | - Corinne Antignac
- INSERM UMR1163, Laboratory of Hereditary Kidney Diseases, Imagine Institute, 24 Boulevard du Montparnasse, 75015, Paris, France.,Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.,Centre de Référence Syndrome Néphrotique Idiopathique de l'enfant et de l'adulte, Paris, France.,Department of Genetics, Assistance Publique-Hôpitaux de Paris, Necker-Enfants malades Hospital, Paris, France
| | - Olivia Boyer
- INSERM UMR1163, Laboratory of Hereditary Kidney Diseases, Imagine Institute, 24 Boulevard du Montparnasse, 75015, Paris, France.,Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.,Department of Pediatric Nephrology, Centre de référence du syndrome néphrotique idiopathique de l'enfant et l'adulte, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades Hospital, Paris, France.,Centre de Référence Syndrome Néphrotique Idiopathique de l'enfant et de l'adulte, Paris, France
| |
Collapse
|
35
|
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.
Collapse
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
| |
Collapse
|
36
|
Changes in DNA methylation in naïve T helper cells regulate the pathophysiological state in minimal-change nephrotic syndrome. BMC Res Notes 2017; 10:480. [PMID: 28915836 PMCID: PMC5603023 DOI: 10.1186/s13104-017-2719-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 07/29/2017] [Indexed: 11/13/2022] Open
Abstract
Background DNA methylation plays a crucial role in regulating transcription, and changes in DNA methylation affect gene expression and disease development. Minimal change nephrotic syndrome (MCNS) has been reported to involve immunological disturbances. Since the characteristic features of the disease include recurrent relapse and sex and age preference, the disease pathogenesis may be partly related to epigenetic changes. However, little is known about these changes. Methods We analyzed genome-wide DNA methylation using the microarray-based integrated analysis of methylation by isoschizomers method. This method was used to evaluate methylation in monocytes (patient number; n = 6) and naïve T helper cells (n = 4) from the peripheral blood of MCNS patients both in relapse and following remission and that of healthy controls (n = 5). Results In total, 85 co-occurring genes were identified in naïve T helper cells, while 4 such genes were identified in monocytes, which were common among the 3 following comparisons for changes in DNA methylation using sample pairs: (1) relapse versus remission, (2) relapse versus controls, and (3) remission versus controls. In 82 of 85 co-occurring genes (96.5%) in naïve T helper cells, the level of DNA methylation was altered according to disease activity, but was not related to disease activity in the 4 genes detected in monocytes. Conclusions Therefore, in 82 co-occurring genes in naïve T helper cells, the regulation of DNA methylation was well correlated with the clinical and pathophysiological state. Our genome-wide approach to analyze DNA methylation provides further insight into the pathogenesis of MCNS and indicates potential prediction and diagnostic tool for the disease. Electronic supplementary material The online version of this article (doi:10.1186/s13104-017-2719-1) contains supplementary material, which is available to authorized users.
Collapse
|
37
|
Wang SF, Chen YH, Chen DQ, Liu ZZ, Xu F, Zeng CH, Hu WX. Mesangial proliferative lupus nephritis with podocytopathy: a special entity of lupus nephritis. Lupus 2017; 27:303-311. [PMID: 28720048 DOI: 10.1177/0961203317720526] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Mesangial proliferative lupus nephritis may coexist with podocytopathy, but its clinical-morphological features, treatment response and outcomes have not been compared with mesangial proliferative lupus nephritis without podocytopathy. In this study, 125 biopsies of lupus nephritis patients showing mesangial proliferation with mesangial immune deposits were collected and divided into podocytopathy group (defined as podocyte foot process effacement (FPE) >50% with nephrotic syndrome (NS)) and mesangial group (FPE ≤50%, or FPE >50% without NS). Mesangial proliferation and tubular- interstitial lesions were semi-quantitatively analyzed. We found that the incidence of renal involvement as the onset symptoms ( P < .001), nephrotic syndrome ( P < .001), acute kidney injury ( P < .001), the degree of acute tubular- interstitial lesions ( P < .001), and renal relapse (51.6% vs. 23.7%, P = .005) were significantly higher in the podocytopathy group than in the mesangial group. In contrast, the incidence of arthritis ( P < .001), fever ( P = .042), low serum C4 ( P = .008) and hematuria ( P = .033) was significantly lower in the podocytopathy group than in the mesangial group. No patients developed end stage renal disease or death during a median follow-up of 64 (interquartile range (IQR) 37-103) months in the podocytopathy group and 53 (IQR 30-83) months in the mesangial group. In conclusion, mesangial proliferative lupus nephritis with and without podocytopathy should be subdivided into two separate classes of lupus nephritis.
Collapse
Affiliation(s)
- S F Wang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital. Nanjing University School of Medicine. Nanjing, China
| | - Y H Chen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital. Nanjing University School of Medicine. Nanjing, China
| | - D Q Chen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital. Nanjing University School of Medicine. Nanjing, China
| | - Z Z Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital. Nanjing University School of Medicine. Nanjing, China
| | - F Xu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital. Nanjing University School of Medicine. Nanjing, China
| | - C H Zeng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital. Nanjing University School of Medicine. Nanjing, China
| | - W X Hu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital. Nanjing University School of Medicine. Nanjing, China
| |
Collapse
|
38
|
Relapse of nephrotic syndrome during post-rituximab peripheral blood B-lymphocyte depletion. Clin Exp Nephrol 2017; 22:110-116. [DOI: 10.1007/s10157-017-1415-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Accepted: 04/16/2017] [Indexed: 12/21/2022]
|
39
|
Abstract
Minimal change disease (MCD) is a major cause of idiopathic nephrotic syndrome (NS), characterized by intense proteinuria leading to edema and intravascular volume depletion. In adults, it accounts for approximately 15% of patients with idiopathic NS, reaching a much higher percentage at younger ages, up to 70%-90% in children >1 year of age. In the pediatric setting, a renal biopsy is usually not performed if presentation is typical and the patient responds to therapy with oral prednisone at conventional doses. Therefore, in this setting steroid-sensitive NS can be considered synonymous with MCD. The pathologic hallmark of disease is absence of visible alterations by light microscopy and effacement of foot processes by electron microscopy. Although the cause is unknown and it is likely that different subgroups of disease recognize a different pathogenesis, immunologic dysregulation and modifications of the podocyte are thought to synergize in altering the integrity of the glomerular basement membrane and therefore determining proteinuria. The mainstay of therapy is prednisone, but steroid-sensitive forms frequently relapse and this leads to a percentage of patients requiring second-line steroid-sparing immunosuppression. The outcome is variable, but forms of MCD that respond to steroids usually do not lead to chronic renal damage, whereas forms that are unresponsive to steroids may subsequently reveal themselves as FSGS. However, in a substantial number of patients the disease is recurrent and requires long-term immunosuppression, with significant morbidity because of side effects. Recent therapeutic advances, such as the use of anti-CD20 antibodies, have provided long-term remission off-therapy and suggest new hypotheses for disease pathogenesis.
Collapse
Affiliation(s)
- Marina Vivarelli
- Division of Nephrology and Dialysis, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy; and
| | - Laura Massella
- Division of Nephrology and Dialysis, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy; and
| | - Barbara Ruggiero
- Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, Ranica, Bergamo, Italy
| | - Francesco Emma
- Division of Nephrology and Dialysis, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy; and
| |
Collapse
|
40
|
Kang HG, Seo H, Lim JH, Kim JI, Han KH, Park HW, Koo JW, Kim KH, Kim JH, Cheong HI, Ha IS. Markers of disease and steroid responsiveness in paediatric idiopathic nephrotic syndrome: Whole-transcriptome sequencing of peripheral blood mononuclear cells. J Int Med Res 2017. [PMID: 28639503 PMCID: PMC5536413 DOI: 10.1177/0300060516652762] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Objective To identify markers of disease and steroid responsiveness in paediatric idiopathic nephrotic syndrome. Methods Whole-transcriptome sequencing was performed of peripheral blood mononuclear cells (PBMCs) from patients with NS. Differentially expressed genes (DEGs) were identified in patients with active NS vs those in remission, and those with steroid-sensitive NS (SSNS) vs steroid-resistant NS (SRNS). Results A total of 1065 DEGs were identified in patients with NS (n = 10) vs those in remission (n = 9). These DEGs correlated with cytokine and/or immune system signalling and the extracellular matrix. Comparisons between SSNS (n = 6) and SRNS (n = 4) identified 1890 DEGs. These markers of steroid responsiveness were enriched with genes related to the cell cycle, targets of microRNAs, and genes related to cytokines. Conclusions Meaningful DEGs were identified. Additional studies with larger numbers of patients will provide more comprehensive data.
Collapse
Affiliation(s)
- Hee Gyung Kang
- 1 Department of Paediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea.,2 Research Coordination Centre for Rare Diseases, Seoul National University Hospital, Seoul, Republic of Korea
| | - Heewon Seo
- 3 Seoul National University Biomedical Informatics, Seoul National University College of Medicine, Seoul, Republic of Korea.,4 Systems Biomedical Informatics Research Centre, Seoul National University, Seoul, Republic of Korea
| | - Jae Hyun Lim
- 3 Seoul National University Biomedical Informatics, Seoul National University College of Medicine, Seoul, Republic of Korea.,4 Systems Biomedical Informatics Research Centre, Seoul National University, Seoul, Republic of Korea
| | - Jong Il Kim
- 5 Genomic Medicine Institute, Seoul National University, Seoul, Republic of Korea
| | - Kyoung Hee Han
- 6 Department of Paediatrics, Jeju University Hospital, Jeju, Korea
| | - Hye Won Park
- 7 Department of Paediatrics, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea
| | - Ja Wook Koo
- 8 Department of Paediatrics, Inje University Sanggye Paik Hospital, Seoul, Republic of Korea
| | - Kee Hyuck Kim
- 9 Department of Paediatrics, National Health Insurance Corporation Ilsan Hospital, Gyeonggi-do, Republic of Korea
| | - Ju Han Kim
- 3 Seoul National University Biomedical Informatics, Seoul National University College of Medicine, Seoul, Republic of Korea.,4 Systems Biomedical Informatics Research Centre, Seoul National University, Seoul, Republic of Korea
| | - Hae Il Cheong
- 1 Department of Paediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea.,2 Research Coordination Centre for Rare Diseases, Seoul National University Hospital, Seoul, Republic of Korea.,10 Kidney Research Institute, Medical Research Centre, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Il-Soo Ha
- 1 Department of Paediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea.,10 Kidney Research Institute, Medical Research Centre, Seoul National University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
41
|
Kunjal R, Adam-Eldien R, Makary R, Jo-Hoy F, Heilig CW. A Unique Cause of Proteinuria in Pregnancy: Class II Lupus Nephritis with Concomitant Minimal Change Disease. Case Rep Nephrol Dial 2016; 6:101-105. [PMID: 27781205 PMCID: PMC5073675 DOI: 10.1159/000448731] [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: 05/26/2016] [Accepted: 07/26/2016] [Indexed: 11/29/2022] Open
Abstract
We report the case of a 22-year-old African American female who presented to another facility for routine follow-up in the 34th week of pregnancy with lower extremity swelling and nephrotic-range proteinuria. Although she was normotensive, it was initially thought that she had preeclampsia. She was monitored carefully and delivery was induced at 37 weeks of gestation. She was transferred to our hospital, where she was diagnosed with systemic lupus erythematosus (SLE) based on clinical and laboratory criteria. Renal biopsy revealed a surprising finding of minimal change disease (MCD) concomitant with class II lupus nephritis (LN). She was managed with pulses and then tapering doses of steroid therapy with dramatic resolution of the nephrotic syndrome. This case demonstrates not only the rare de novo occurrence of SLE in pregnancy, but the unique finding of MCD coexisting with class II LN. We propose that altered T cell activity may be the link between these seemingly distinct entities.
Collapse
Affiliation(s)
- Ryan Kunjal
- Department of Internal Medicine, University of Florida College of Medicine, Jacksonville, Fla., USA
| | - Rabie Adam-Eldien
- Department of Nephrology, University of Florida College of Medicine, Jacksonville, Fla., USA
| | - Raafat Makary
- Department of Pathology, University of Florida College of Medicine, Jacksonville, Fla., USA
| | - Francois Jo-Hoy
- Department of Internal Medicine, University of Florida College of Medicine, Jacksonville, Fla., USA
| | - Charles W Heilig
- Department of Nephrology, University of Florida College of Medicine, Jacksonville, Fla., USA
| |
Collapse
|
42
|
Minimal change disease and idiopathic FSGS: manifestations of the same disease. Nat Rev Nephrol 2016; 12:768-776. [DOI: 10.1038/nrneph.2016.147] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
43
|
Xu Y, Lin H, Zheng W, Ye X, Yu L, Zhuang J, Yang Q, Wang D. Matrine ameliorates adriamycin-induced nephropathy in rats by enhancing renal function and modulating Th17/Treg balance. Eur J Pharmacol 2016; 791:491-501. [PMID: 27640745 DOI: 10.1016/j.ejphar.2016.09.022] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Revised: 09/04/2016] [Accepted: 09/14/2016] [Indexed: 02/07/2023]
Abstract
Matrine (MAT) is an active alkaloid extracted from Radix Sophora flavescens. The present study was to investigate whether MAT could effectively treat Adriamycin-induced nephropathy (AIN). AIN was induced in rats using a single injection of Adriamycin (ADR). Renal interleukin-6 (IL-6), IL-10, IL-17 and transforming growth factor-β (TGF-β) levels, and the expression of forkhead box protein 3 (Foxp3) and retinoid-related orphan nuclear receptor γt (Rorγt) was measured. AIN rats developed severe albuminuria, hypoalbuminaemia, hyperlipidaemia and podocyte injury. Daily administration of MAT (100mg/kg or 200mg/kg) significantly prevented ADR-induced podocyte injury, decreased AIN symptoms and improved renal pathology manifestations. Of note, treatment with MAT (100mg/kg) plus prednisone (Pre, 5mg/kg) had equivalent efficacy to that of Pre alone (10mg/kg). Additional findings showed that ADR triggered a disordered cytokine network and abnormal expression of Foxp3 and Rorγt in rats, as reflected by increased levels of IL-6, IL-10, TGF-β, Rorγt and decreased levels of IL-10 and Foxp3. Interestingly, MAT weakened the disordered cytokine network and normalized the expression of Foxp3 and Rorγt. In addition, a significant negative correlation was observed between the values of Foxp3/Rorγt and renal pathology scores. Finally, MAT normalized regulatory T cells (Treg)/ T-helper17 cells (Th17) ratio in peripheral blood mononuclear cells of AIN rats. These data indicate MAT prevents AIN through the modification of disordered plasma lipids and recovery of renal function, and this bioactivity is at least partly attributed to the suppression of renal inflammation and the regulation of the Treg/Th17 imbalance.
Collapse
Affiliation(s)
- Yixiao Xu
- Department of Pediatrics, the Second Affiliated & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Department of Pathophysiology, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Hongzhou Lin
- Department of Pediatrics, the Second Affiliated & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Wenjie Zheng
- Department of Pediatrics, the Second Affiliated & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Xiaohua Ye
- Department of Pediatrics, the Second Affiliated & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Lingfang Yu
- Department of Pediatrics, the Second Affiliated & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Jieqiu Zhuang
- Department of Pediatrics, the Second Affiliated & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Qing Yang
- Department of Pediatrics, the Second Affiliated & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Dexuan Wang
- Department of Pediatrics, the Second Affiliated & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
| |
Collapse
|
44
|
Zea AH, Stewart T, Ascani J, Tate DJ, Finkel-Jimenez B, Wilk A, Reiss K, Smoyer WE, Aviles DH. Activation of the IL-2 Receptor in Podocytes: A Potential Mechanism for Podocyte Injury in Idiopathic Nephrotic Syndrome? PLoS One 2016; 11:e0157907. [PMID: 27389192 PMCID: PMC4936730 DOI: 10.1371/journal.pone.0157907] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 06/07/2016] [Indexed: 12/16/2022] Open
Abstract
The renal podocyte plays an important role in maintaining the structural integrity of the glomerular basement membrane. We have previously reported that patients with idiopathic nephrotic syndrome (INS) have increased IL-2 production. We hypothesized that podocytes express an IL-2 receptor (IL-2R) and signaling through this receptor can result in podocyte injury. To confirm the presence of the IL-2R, we tested a conditionally immortalized murine podocyte cell line by flow cytometry, qPCR, and Western blot. To test for the presence of the IL-2R in vivo, immunohistochemical staining was performed on human renal biopsies in children with FSGS and control. Podocytes were stimulated with IL-2 in vitro, to study signaling events via the JAK/STAT pathway. The results showed that stimulation with IL-2 resulted in increased mRNA and protein expression of STAT 5a, phosphorylated STAT 5, JAK 3, and phosphorylated JAK 3. We then investigated for signs of cellular injury and the data showed that pro-apoptotic markers Bax and cFLIP were significantly increased following IL-2 exposure, whereas LC3 II was decreased. Furthermore, mitochondrial depolarization and apoptosis were both significantly increased following activation of the IL-2R. We used a paracellular permeability assay to monitor the structural integrity of a podocyte monolayer following IL-2 exposure. The results showed that podocytes exposed to IL-2 have increased albumin leakage across the monolayer. We conclude that murine podocytes express the IL-2R, and that activation through the IL-2R results in podocyte injury.
Collapse
Affiliation(s)
- Arnold H. Zea
- Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Tyrus Stewart
- Department of Pediatric Nephrology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Jeannine Ascani
- Department of Research Ochsner Biobank, Ochsner Health System, New Orleans, Louisiana, United States of America
| | - David J. Tate
- Eurofins Central Analytical Laboratories, New Orleans, Louisiana, United States of America
| | - Beatriz Finkel-Jimenez
- Department of Medical Microbiology and Immunology, American University of the Caribbean School of Medicine, Coral Gables, Florida, United States of America
| | - Anna Wilk
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Krzysztof Reiss
- Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - William E. Smoyer
- Department of Nephrology, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Diego H. Aviles
- Department of Pediatric Nephrology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America
| |
Collapse
|
45
|
Qiao Y, Berg AL, Wang P, Ge Y, Quan S, Zhou S, Wang H, Liu Z, Gong R. MC1R is dispensable for the proteinuria reducing and glomerular protective effect of melanocortin therapy. Sci Rep 2016; 6:27589. [PMID: 27270328 PMCID: PMC4897792 DOI: 10.1038/srep27589] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 05/17/2016] [Indexed: 12/21/2022] Open
Abstract
Melanocortin therapy by using adrenocorticotropic hormone (ACTH) or non-steroidogenic melanocortin peptides attenuates proteinuria and glomerular injury in experimental glomerular diseases and induces remission of nephrotic syndrome in patients with diverse glomerulopathies, even those resistant to steroids. The underlying mechanism remains elusive, but the role of melanocortin 1 receptor (MC1R) has been implicated and was examined here. Four patients with congenital red hair color and nephrotic syndrome caused by idiopathic membranous nephropathy or focal segmental glomerulosclerosis were confirmed by gene sequencing to bear dominant-negative MC1R mutations. Despite prior corticosteroid resistance, all patients responded to ACTH monotherapy and ultimately achieved clinical remission, inferring a steroidogenic-independent and MC1R-dispensable anti-proteinuric effect of melanocortin signaling. In confirmatory animal studies, the protective effect of [Nle4, D-Phe7]-α-melanocyte stimulating hormone (NDP-MSH), a potent non-steroidogenic pan-melanocortin receptor agonist, on the lipopolysaccharide elicited podocytopathy was completely preserved in MC1R-null mice, marked by reduced albuminuria and diminished histologic signs of podocyte injury. Moreover, in complementary in vitro studies, NDP-MSH attenuated the lipopolysaccharide elicited apoptosis, hypermotility and impairment of filtration barrier function equally in primary podocytes derived from MC1R-null and wild-type mice. Collectively, our findings suggest that melanocortin therapy confers a proteinuria reducing and podoprotective effect in proteinuric glomerulopathies via MC1R-independent mechanisms.
Collapse
Affiliation(s)
- Yingjin Qiao
- Institute of Nephrology, Blood Purification Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA
| | - Anna-Lena Berg
- Department of Nephrology, Lund University Hospital, Lund, Sweden
| | - Pei Wang
- Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA
| | - Yan Ge
- Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA
| | - Songxia Quan
- Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA
| | - Sijie Zhou
- Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA
| | - Hai Wang
- Department of Pathology, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA
| | - Zhangsuo Liu
- Institute of Nephrology, Blood Purification Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Rujun Gong
- Division of Kidney Disease and Hypertension, Department of Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island, USA
| |
Collapse
|
46
|
Bertelli R, Bonanni A, Di Donato A, Cioni M, Ravani P, Ghiggeri GM. Regulatory T cells and minimal change nephropathy: in the midst of a complex network. Clin Exp Immunol 2015; 183:166-74. [PMID: 26147676 DOI: 10.1111/cei.12675] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2015] [Indexed: 12/16/2022] Open
Abstract
Minimal change nephrosis (MCN) is an important cause of morbidity in children. In spite of successful therapies having been developed in the last three decades, most aspects related to pathogenesis still remain poorly defined. Evolution in basic immunology and results deriving from animal models of the disease suggest a complex interaction of factors and cells starting from activation of innate immunity and continuing with antigen presentation. Oxidants, CD80 and CD40/CD40L have probably a relevant role at the start. Studies in animal models and in human beings also suggest the possibility that the same molecules (i.e. CD80, CD40) are expressed by podocytes under inflammatory stimuli, representing a direct potential mechanism for proteinuria. B and T cells could play a relevant role this contest. Implication of B cells is suggested indirectly by studies utilizing anti-CD20 monoclonal antibodies as the main therapy. The role of regulatory T cells (Tregs ) is supported mainly by results in animal models of nephrotic syndrome (i.e. adriamycin, puromycin, lipopolysaccharide), showing a protective effect of direct Treg infusion or stimulation by interleukin 2 (IL-2). Limited studies have also shown reduced amounts of circulating Tregs in patients with active MCN cells. The route from bench to bedside would be reduced if results from animal models were confirmed in human pathology. The expansion of Tregs with recombinant IL-2 and new anti-CD20 monoclonal antibodies is the beginning. Blocking antigen-presenting cells with cytotoxic T lymphocyte antigen (CTLA-4)-Ig fusion molecules inhibiting CD80 and/or with blockers of CD40-CD40 ligand interaction represent potential new approaches. The hope is that evolution in therapies of MCN could fill a gap lasting 30 years.
Collapse
Affiliation(s)
- R Bertelli
- Laboratory on Physiopathology of Uremia, Children's Hospital, Genoa, Italy.,Division of Nephrology, Dialysis, Transplantation, Giannina Gaslini Children's Hospital, Genoa, Italy
| | - A Bonanni
- Laboratory on Physiopathology of Uremia, Children's Hospital, Genoa, Italy.,Division of Nephrology, Dialysis, Transplantation, Giannina Gaslini Children's Hospital, Genoa, Italy
| | - A Di Donato
- Laboratory on Physiopathology of Uremia, Children's Hospital, Genoa, Italy.,Division of Nephrology, Dialysis, Transplantation, Giannina Gaslini Children's Hospital, Genoa, Italy
| | - M Cioni
- Laboratory on Physiopathology of Uremia, Children's Hospital, Genoa, Italy.,Division of Nephrology, Dialysis, Transplantation, Giannina Gaslini Children's Hospital, Genoa, Italy
| | - P Ravani
- Division of Nephrology, University of Calgary, Calgary, Canada
| | - G M Ghiggeri
- Laboratory on Physiopathology of Uremia, Children's Hospital, Genoa, Italy.,Division of Nephrology, Dialysis, Transplantation, Giannina Gaslini Children's Hospital, Genoa, Italy
| |
Collapse
|
47
|
Tsai IJ, Chou CH, Yang YH, Lin WC, Lin YH, Chow LP, Lee HH, Kao PG, Liau WT, Jou TS, Tsau YK. Inhibition of Rho-associated kinase relieves C5a-induced proteinuria in murine nephrotic syndrome. Cell Mol Life Sci 2015; 72:3157-71. [PMID: 25790939 PMCID: PMC11113791 DOI: 10.1007/s00018-015-1888-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2014] [Revised: 02/14/2015] [Accepted: 03/13/2015] [Indexed: 02/05/2023]
Abstract
Childhood nephrotic syndrome is mainly caused by minimal change disease which is named because only subtle ultrastructural alteration could be observed at electron microscopic level in the pathological kidney. Glomerular podocytes are presumed to be the target cells whose protein sieving capability is compromised by a yet unidentified permeability perturbing factor. In a cohort of children with non-hereditary idiopathic nephrotic syndrome, we found the complement fragment C5a was elevated in their sera during active disease. Administration of recombinant C5a induced profound proteinuria and minimal change nephrotic syndrome in mice. Purified glomerular endothelial cells, instead of podocytes, were demonstrated to be responsible for the proteinuric effect elicited by C5a. Further studies depicted a signaling pathway involving Rho/Rho-associated kinase/myosin activation leading to endothelial cell contraction and cell adhesion complex breakdown. Significantly, application of Rho-associated kinase inhibitor, Y27632, prevented the protein leaking effects observed in both C5a-treated purified endothelial cells and mice. Taken together, our study identifies a previously unknown mechanism underlying nephrotic syndrome and provides a new insight toward identifying Rho-associated kinase inhibition as an alternative therapeutic option for nephrotic syndrome.
Collapse
Affiliation(s)
- I-Jung Tsai
- Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chia-Hung Chou
- Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yao-Hsu Yang
- Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wei-Chou Lin
- Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yen-Hung Lin
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Lu-Ping Chow
- Graduate Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hsiao-Hui Lee
- Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Pei-Gang Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Wan-Ting Liau
- Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tzuu-Shuh Jou
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yong-Kwei Tsau
- Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| |
Collapse
|
48
|
Maas RJ, Deegens JK, Wetzels JF. Permeability factors in idiopathic nephrotic syndrome: historical perspectives and lessons for the future. Nephrol Dial Transplant 2015; 29:2207-16. [PMID: 25416821 DOI: 10.1093/ndt/gfu355] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The term idiopathic nephrotic syndrome (iNS) traditionally covers minimal change disease and primary focal segmental glomerulosclerosis (FSGS), now thought to be separate disease entities. Clinical and experimental evidence suggest that circulating permeability factors are involved in their pathogenesis. In the past four decades, many investigators have searched for the responsible factors, thus far with little success. The recent report of the soluble urokinase plasminogen activator receptor as a causative factor in FSGS has received much attention, but again the initially promising findings were not confirmed. We describe the history of the search for permeability factors, discuss the pitfalls that are likely responsible for the lack of success and propose criteria that should be used in future studies when evaluating candidate permeability factors.
Collapse
Affiliation(s)
- Rutger J Maas
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jeroen K Deegens
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jack F Wetzels
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| |
Collapse
|
49
|
Kaneko K, Tsuji S, Kimata T, Kitao T, Yamanouchi S, Kato S. Pathogenesis of childhood idiopathic nephrotic syndrome: a paradigm shift from T-cells to podocytes. World J Pediatr 2015; 11:21-8. [PMID: 25822700 DOI: 10.1007/s12519-015-0003-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 07/11/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Nephrotic syndrome is the most common cause of kidney disease in children, but its pathogenesis remains unclear. This article reviews the novel aspects of the mechanisms underlying massive proteinuria in minimal-change disease, which is the most common form of childhood nephrotic syndrome. DATA SOURCES This article integrates the findings of a PubMed database search for English language articles published in the past 40 years (from September 1974 to February 2014) using the key words "pathogenesis", "minimal change nephrotic syndrome" or "idiopathic nephrotic syndrome". RESULTS Unknown humoral factors associated with T-cell dysfunction have been thought to play an important role in the pathogenesis of minimal-change disease. However, recent findings are changing this paradigm, i.e., visceral glomerular epithelial cells (podocytes) may be involved via expression of molecules such as CD80 and angiopoietin-like 4. CONCLUSIONS Recent evidence suggests that minimal-change disease results from interactions between humoral factors and dysfunctional podocytes. In addition to immunosuppressant drugs that target lymphocytes, a biological agent such as an antibody against the abnormal molecule(s) expressed by podocytes may provide novel drug treatment for minimal-change disease.
Collapse
Affiliation(s)
- Kazunari Kaneko
- Department of Pediatrics, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan,
| | | | | | | | | | | |
Collapse
|
50
|
Yılmaz D, Yenigün A, Sönmez F, Kurt Ömürlü İ. Evaluation of children with steroid-sensitive nephrotic syndrome in terms of allergies. Ren Fail 2015; 37:387-91. [PMID: 25598239 DOI: 10.3109/0886022x.2014.996087] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The etiology of minimal-change disease is not fully known, it is believed to be mediated by the immune system. Minimal-change disease also reported as having association with atopy. In this study, atopy history, the levels of serum IgE, and skin prick test in children with steroid-sensitive nephrotic syndrome were investigated. METHODS A group of 30 children (mean age 7.7 ± 2.2 years, 56.6% male) diagnosed with steroid-sensitive nephrotic syndrome were included in the study. Serum immunoglobulin E levels and eosinophil counts were evaluated in children with steroid-sensitive nephrotic syndrome both in relapse and remission. Skin prick test was performed in remission. RESULTS Of the 30 children investigated, 11 (36.7%) had a history of atopy. The median serum total IgE levels in nephrotic children in relapse, with (445 IU/mL) and without atopy (310 IU/mL) were significantly higher than those in remission (respectively, 200 IU/mL, p = 0.021, and 42 IU/mL, p = 0.001). The skin prick tests for all the allergens were evaluated as negative in all the patients. CONCLUSION It was thought that increased IgE may reflect the activation of immune mechanism following various stimuli rather than a direct association with atopy in children with steroid-sensitive nephrotic syndrome.
Collapse
Affiliation(s)
- Dilek Yılmaz
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine , Adnan Menderes University, Aydın , Turkey
| | | | | | | |
Collapse
|