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Venkatachalapathy Y, Suresh PKK, Balraj TH, Venkatesan V, Geminiganesan S, C D MP. Clinico-demographic and biochemical correlation of inflammatory gene expression in pediatric nephrotic syndrome. Mol Biol Rep 2024; 51:854. [PMID: 39060482 DOI: 10.1007/s11033-024-09784-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/05/2024] [Indexed: 07/28/2024]
Abstract
BACKGROUND Nephrotic syndrome (NS) is a common kidney disease in children. While Steroid-Sensitive Nephrotic Syndrome (SSNS) is frequently observed, Steroid-Resistant Nephrotic Syndrome (SRNS) has a poor prognosis and often leads to chronic kidney disease. The pathogenesis of SRNS is complex, with immunological modulation of T helper subtypes 1 and 2 cytokines increasing susceptibility to the disease. Currently, no established biomarkers can accurately predict SRNS. However, a group of cytokines might serve as potential indicators of responsiveness, aiding in the identification of patients with SRNS. The discovery of these cytokines as novel biomarkers for early diagnosis could greatly benefit patients. This includes preventing the adverse effects of glucocorticoid treatment and enabling a timely transition to more effective therapeutic alternatives. METHODS This study aims to investigate the association between the gene expression patterns of cytokines, including IL-2, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, IL-17A, NF-κB, and TNFα, in healthy participants (n = 100), SSNS patients (n = 100), and SRNS patients (n = 100). Using qRT-PCR, followed by Receiver-operating characteristic analysis, the study assesses their potential as biomarkers. Additionally, clinicodemographic data were analyzed, and bioinformatic analyses such as coexpression analysis, gene enrichment, pathway analysis, and Cytoscape were performed to enhance our understanding of the inflammatory cascade initiating podocyte injury in NS. RESULTS The results of our study suggest that specific candidate genes, including IL-2, IL-5, IL-6, IL-9, IL-17A, IL-10, IL-13, and TNFα, exhibit upregulation and hold significant importance, with an Area Under the Curve value of 0.9. CONCLUSION These genes have the potential to serve as valuable prognostic and management tools for NS, forming a promising panel of inflammatory gene biomarkers. Furthermore, conducting an extensive analysis that integrates cytokine genes with their respective targeted microRNAs could offer deeper insights into the pathogenesis of the disease.
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Affiliation(s)
| | | | - Thendral Hepsibha Balraj
- Department of Biochemistry, Ethiraj College for Women, Affiliated to University of Madras, Chennai, India
| | - Vettriselvi Venkatesan
- Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
| | - Sangeetha Geminiganesan
- Department of Paediatric Medicine, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
| | - Mohana Priya C D
- Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research, Chennai, India.
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Nishino T, Tomori S, Ono S, Takahashi K, Mimaki M. Effect of proteinuria at relapse on shear wave velocity assessed using ultrasound elastography in children with idiopathic nephrotic syndrome. J Med Ultrason (2001) 2024; 51:491-496. [PMID: 38613718 DOI: 10.1007/s10396-024-01455-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 03/30/2024] [Indexed: 04/15/2024]
Abstract
PURPOSE Shear wave velocity (SWV) is an ultrasound elastography technique that provides much information for kidney disease assessment. However, the factors that alter SWV are not fully understood; it is unclear whether the variation in SWV seen in proteinuria associated with disease progression is due to tissue or proteinuria. This study investigated the effect of proteinuria on SWV. METHODS This prospective observational study compared SWV at remission with SWV at relapse in children treated for idiopathic nephrotic syndrome (INS) between April 2020 and December 2023. All relapses without oral steroids during the observation period were measured. SWV at remission was defined as the date closest to relapse during which repeated measurements were taken approximately every 3 months after steroid discontinuation. RESULTS Eight patients were treated for INS with a median observation period of 21.9 months (11.8-27.1). Of the 15 relapses, five that met the definition were considered for the study. The median interval between the measurement at relapse and remission was 40 days (11-55). SWV was significantly lower at relapse than remission (2.40 ± 0.20 m/s vs. 2.14 ± 0.15 m/s, P < 0.01). CONCLUSIONS SWV decreased in the presence of severe proteinuria at relapse compared to the remission measurements. Although more cases need to be studied, the decrease in SWV may reflect the mechanism by which protein leaks into the urine, not just a direct change caused by the presence of proteinuria.
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Affiliation(s)
- Tomohiko Nishino
- Department of Pediatrics, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-Ku, Tokyo, 173-8605, Japan.
| | - Shinya Tomori
- Department of Pediatrics, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-Ku, Tokyo, 173-8605, Japan
| | - Sayaka Ono
- Department of Pediatrics, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-Ku, Tokyo, 173-8605, Japan
| | - Kazuhiro Takahashi
- Department of Pediatrics, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-Ku, Tokyo, 173-8605, Japan
| | - Masakazu Mimaki
- Department of Pediatrics, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-Ku, Tokyo, 173-8605, Japan
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Furuie K, Kuraoka S, Ban H, Hidaka Y, Nagata H, Tamura H, Nagano K, Kawano T, Furuse A, Nakazato H, Nakamura K. Ongoing impacts of childhood-onset glomerular diseases during young adulthood. Pediatr Nephrol 2024; 39:1791-1799. [PMID: 38110662 PMCID: PMC11026251 DOI: 10.1007/s00467-023-06250-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/29/2023] [Accepted: 11/29/2023] [Indexed: 12/20/2023]
Abstract
BACKGROUND Childhood-onset glomerular disease often requires ongoing treatment and follow-up into adulthood. However, few studies have analyzed the associated impact and distress experienced by patients with this condition during the transition from childhood to adolescence and adulthood. METHODS At three facilities, we recruited patients who developed idiopathic nephrotic syndrome or IgA nephropathy during childhood and were at least 18 years old at the time of study entry. Among them, a questionnaire-based survey was administered to patients who consented to participate, and the results were analyzed in conjunction with clinical information. RESULTS Data from a total of 38 patients were analyzed. Of these patients, 15 had idiopathic nephrotic syndrome and 23 had IgA nephropathy. The age of transition from pediatrics to the adult medicine department was correlated with the number of recurrences. Many patients also reported being significantly affected by exercise restrictions and physical decline associated with their diseases and medications. Various impacts, including distress, affected decision-making regarding higher education, with patients engaging in higher education at a significantly higher rate compared with the regional average (66.7% vs. 46.9%, p = 0.028). CONCLUSION We analyzed the impact of childhood-onset glomerular disease and distress during the transition period from pediatric to adult care. This study highlighted the significant impact of medications and exercise restrictions on patients' decisions regarding higher education. Future prospective studies will be needed to examine patients' distress in more detail and establish management approaches to enhance patient quality of life.
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Affiliation(s)
- Keishiro Furuie
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, 860-8556, Japan
| | - Shohei Kuraoka
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, 860-8556, Japan.
| | - Hideki Ban
- Department of Pediatrics, Japanese Red Cross Kumamoto Hospital, Kumamoto City, Japan
| | - Yuko Hidaka
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, 860-8556, Japan
| | - Hiroko Nagata
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, 860-8556, Japan
| | - Hiroshi Tamura
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, 860-8556, Japan
| | - Koji Nagano
- Department of Pediatrics, Kumamoto Chuo Hospital, Kumamoto City, Japan
| | - Tomoyasu Kawano
- Department of Pediatrics, Kumamoto Chuo Hospital, Kumamoto City, Japan
| | - Akio Furuse
- Department of Pediatrics, Japanese Red Cross Kumamoto Hospital, Kumamoto City, Japan
| | - Hitoshi Nakazato
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, 860-8556, Japan
| | - Kimitoshi Nakamura
- Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto City, 860-8556, Japan
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Li T, Ma X, Wang T, Tian W, Liu J, Shen W, Liu Y, Li Y, Zhang X, Ma J, Zhang X, Ma J, Wang H. Clostridium butyricum inhibits the inflammation in children with primary nephrotic syndrome by regulating Th17/Tregs balance via gut-kidney axis. BMC Microbiol 2024; 24:97. [PMID: 38521894 PMCID: PMC10960420 DOI: 10.1186/s12866-024-03242-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 02/27/2024] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Primary nephrotic syndrome (PNS) is a common glomerular disease in children. Clostridium butyricum (C. butyricum), a probiotic producing butyric acid, exerts effective in regulating inflammation. This study was designed to elucidate the effect of C. butyricum on PNS inflammation through the gut-kidney axis. METHOD BALB/c mice were randomly divided into 4 groups: normal control group (CON), C. butyricum control group (CON+C. butyricum), PNS model group (PNS), and PNS with C. butyricum group (PNS+C. butyricum). The PNS model was established by a single injection of doxorubicin hydrochloride (DOX) through the tail vein. After 1 week of modeling, the mice were treated with C. butyricum for 6 weeks. At the end of the experiment, the mice were euthanized and associated indications were investigated. RESULTS Since the successful modeling of the PNS, the 24 h urine protein, blood urea nitrogen (BUN), serum creatinine (SCr), urine urea nitrogen (UUN), urine creatinine (UCr), lipopolysaccharides (LPS), pro-inflammatory interleukin (IL)-6, IL-17A were increased, the kidney pathological damage was aggravated, while a reduction of body weights of the mice and the anti-inflammatory IL-10 significantly reduced. However, these abnormalities could be dramatically reversed by C. butyricum treatment. The crucial Th17/Tregs axis in PNS inflammation also was proved to be effectively regulated by C. butyricum treatment. This probiotic intervention notably affected the expression levels of signal transducer and activator of transcription 3 (STAT3), Heme oxygenase-1 (HO-1) protein, and retinoic acid-related orphan receptor gamma t (RORγt). 16S rRNA sequencing showed that C. butyricum could regulate the composition of the intestinal microbial community and found Proteobacteria was more abundant in urine microorganisms in mice with PNS. Short-chain fatty acids (SCFAs) were measured and showed that C. butyricum treatment increased the contents of acetic acid, propionic acid, butyric acid in feces, acetic acid, and valeric acid in urine. Correlation analysis showed that there was a closely complicated correlation among inflammatory indicators, metabolic indicators, microbiota, and associated metabolic SCFAs in the gut-kidney axis. CONCLUSION C. butyricum regulates Th17/Tregs balance via the gut-kidney axis to suppress the immune inflammatory response in mice with PNS, which may potentially contribute to a safe and inexpensive therapeutic agent for PNS.
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Affiliation(s)
- Ting Li
- Department of Pediatrics, The First Clinical College of Ningxia Medical University, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Xiaolong Ma
- Department of Pediatrics, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Ting Wang
- Department of Human Anatomy and Histology and Embryology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Wenyan Tian
- Department of Gastroenterology, The First Clinical College of Ningxia Medical University, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Jian Liu
- Department of Hepatobiliary, The First Clinical College of Ningxia Medical University, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Wenke Shen
- Department of Pathogenic Biology and Medical Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Yuanyuan Liu
- Department of Human Anatomy and Histology and Embryology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Yiwei Li
- Department of Human Anatomy and Histology and Embryology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Xiaoxu Zhang
- Department of Gastroenterology, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Junbai Ma
- Department of Pathogenic Biology and Medical Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Xiaoxia Zhang
- College of Traditional Chinese Medicine, Ningxia Medical University, Yinchuan, China.
| | - Jinhai Ma
- Department of Pediatrics, General Hospital of Ningxia Medical University, Yinchuan, 750004, China.
| | - Hao Wang
- Department of Pathogenic Biology and Medical Immunology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
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Yazılıtaş F, Kargın Çakıcı E, Karakaya D, Güngör T, Çelikkaya E, Bülbül M. Evaluation of immature granulocyte percentage and count in pediatric nephrotic syndrome. Postgrad Med 2024; 136:36-43. [PMID: 38197239 DOI: 10.1080/00325481.2024.2303973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 01/04/2024] [Indexed: 01/11/2024]
Abstract
OBJECTIVE The importance of immature granulocytes (IGs) in most infectious and inflammatory diseases has been highlighted. This study aimed to determine the clinical usability and importance of changes in the peripheral complete blood count profile, including IG percentage (IG%) and IG count (IG#), during the relapse and remission phases in pediatric nephrotic syndrome (NS) patients. METHODS This retrospective observational study was performed at a tertiary care hospital between February 2020 and August 2022. Demographic characteristics and laboratory parameters were recorded. The IG count and IG% were measured using an automated hematological analyzer. RESULTS IG% and IG# were both higher during the relapse phase of NS than during the remission phase (0.29% ± 0.14%, versus 0.23% ± 0.14%, p = 0.037 and 0.027 ± 0.015 × 103/µL, versus 0.018 ± 0.014 × 103/µL, p = 0.005, respectively). The neutrophil to lymphocyte ratio (NLR), platelet (PLT), white blood cell (WBC), and neutrophil counts had a strong positive correlation with IG# (r = 0.397, p < 0.001; r = 0.352, p < 0.001; r = 0.622, p < 0.001; r = 0.660, p < 0.001, respectively). The NLR, PLT, WBC, and neutrophil counts had a strong positive correlation with IG% (r = 0.348, p < 0.001; r = 0.187, p = 0.039; r = 0.303, p = 0.001; r = 0.426, p < 0.001, respectively). Receiver operating characteristic curve analysis showed that IG# had the best AUC value of 0.69 (95% CI: 0.58-0.77; p = 0.001) for the relapse phase of NS with a cutoff value of 0.025 × 103/µL (sensitivity: 81.0%, specificity: 78.1%). CONCLUSIONS It is probable that a high level of immature granulocyte count has a positive correlation for NS relapse in pediatric patients. The IG % and IG# can be used together as biomarkers of inflammation in pediatric NS relapse.
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Affiliation(s)
- Fatma Yazılıtaş
- Nephrology Department, SBU Ankara Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Evrim Kargın Çakıcı
- Pediatric Nephrology Department, SBU Ankara Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Deniz Karakaya
- Pediatric Nephrology Department, SBU Ankara Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Tülin Güngör
- Pediatric Nephrology Department, SBU Ankara Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Evra Çelikkaya
- Pediatric Nephrology Department, SBU Ankara Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital, Ankara, Turkey
| | - Mehmet Bülbül
- Pediatric Nephrology and Rheumatology Department, SBU Ankara Dr Sami Ulus Maternity Child Health and Diseases Training and Research Hospital, Ankara, Turkey
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Merchant K, Zanos S, Datta-Chaudhuri T, Deutschman CS, Sethna CB. Transcutaneous auricular vagus nerve stimulation (taVNS) for the treatment of pediatric nephrotic syndrome: a pilot study. Bioelectron Med 2022; 8:1. [PMID: 35078538 PMCID: PMC8790887 DOI: 10.1186/s42234-021-00084-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/14/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Children with frequently relapsing nephrotic syndrome (FRNS) and steroid resistant nephrotic syndrome (SRNS) are exposed to immunosuppressant medications with adverse side effects and variable efficacy. Transcutaneous auricular vagus nerve stimulation (taVNS) modulates the immune system via the inflammatory reflex and has become a therapy of interest for treating immune-mediated illnesses. METHODS An open-label, pilot study of tavNS for five minutes daily for 26 weeks via a TENS 7000 unit was conducted. RESULTS Three FRNS participants and 4 SRNS participants had a mean age of 9.5±4.2 years (range 4 to 17). Those with FRNS remained relapse-free during the study period; two participants continued treatment and remained in remission for 15 and 21 months, respectively. Three SRNS participants experienced a reduction in first morning UPC (mean of 42%, range 25-76%). Although UPC decreased (13.7%) in one SRNS participant with congenital nephrotic syndrome, UPC remained in nephrotic range. All but one participant (non-compliant with treatment) experienced a reduction in TNF (7.33pg/mL vs. 5.46pg/mL, p=0.03). No adverse events or side effects were reported. CONCLUSIONS taVNS was associated with clinical remission in FRNS and moderately reduced proteinuria in non-congenital SRNS. Further study of taVNS as a treatment for nephrotic syndrome in children is warranted. ClinicalTrials.gov Identifier: NCT04169776, Registered November 20, 2019, https://clinicaltrials.gov/ct2/show/NCT04169776 .
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Affiliation(s)
- Kumail Merchant
- Cohen Children's Medical Center of New York, New Hyde Park, United States, NY
| | - Stavros Zanos
- The Feinstein Institutes for Medical Research, Manhasset, United States, NY
| | | | - Clifford S Deutschman
- Cohen Children's Medical Center of New York, New Hyde Park, United States, NY
- The Feinstein Institutes for Medical Research, Manhasset, United States, NY
| | - Christine B Sethna
- Cohen Children's Medical Center of New York, New Hyde Park, United States, NY.
- The Feinstein Institutes for Medical Research, Manhasset, United States, NY.
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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.
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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
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Tamura H. Trends in pediatric nephrotic syndrome. World J Nephrol 2021; 10:88-100. [PMID: 34631479 PMCID: PMC8477269 DOI: 10.5527/wjn.v10.i5.88] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/15/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Nephrotic syndrome (NS) is relatively common in children, with most of its histological types being minimal changed disease. Its etiology has long been attributed to lymphocyte (especially T-cell) dysfunction, while T-cell-mediated vascular hyperpermeability increases protein permeability in glomerular capillaries, leading to proteinuria and hypoproteinemia. Based on this etiology, steroids and immunosuppressive drugs that are effective against this disease have also been considered to correct T-cell dysfunction. However, in recent years, this has been questioned. The primary cause of NS has been considered damage to glomerular epithelial cells and podocyte-related proteins. Therefore, we first describe the changes in expression of molecules involved in NS etiology, and then describe the mechanism by which abnormal expression of these molecules induces proteinuria. Finally, we consider the mechanism by which infection causes the recurrence of NS.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
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Chen J, Qiao XH, Mao JH. Immunopathogenesis of idiopathic nephrotic syndrome in children: two sides of the coin. World J Pediatr 2021; 17:115-122. [PMID: 33660135 DOI: 10.1007/s12519-020-00400-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 11/25/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Idiopathic nephrotic syndrome is a common form of glomerular nephropathy in children, with an incidence rate of 1.15-16.9/100,000 depending on different nationalities and ethnicities. The etiological factors and mechanisms of childhood idiopathic nephrotic syndrome have not yet been fully elucidated. This review summarizes the progress of the immunopathogenesis of idiopathic nephrotic syndrome in children. DATA SOURCES We review the literature on the immunopathogenesis of idiopathic nephrotic syndrome in children. Databases including Medline, Scopus, and Web of Science were searched for studies published in any language with the terms "children", "idiopathic nephrotic syndrome", "immunopathogenesis", "T cells", "circulating permeability factors", and "B cells". RESULTS Dysfunction in T lymphocytes and pathogenic circulatory factors were indicated to play key roles in the pathogenesis of idiopathic nephrotic syndrome. Recently, some studies have shown that cellular immune dysfunction may also be involved in the pathogenesis of idiopathic nephrotic syndrome. CONCLUSIONS Both T- and B-cell dysfunction may play significant roles in the pathogenesis of idiopathic nephrotic syndrome, like two sides of one coin, but the role of B cell seems more important than T cells.
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Affiliation(s)
- Jing Chen
- Department of Nephrology, Ningbo Women and Children's Hospital, 339 LiutingRd, Ningbo, 315012, China
| | - Xiao-Hui Qiao
- Department of Nephrology, Ningbo Women and Children's Hospital, 339 LiutingRd, Ningbo, 315012, China.
| | - Jian-Hua Mao
- Department of Nephrology, Children's Hospital, Zhejiang University School of Medicine, 57 Zhuganxiang, Hangzhou, 310003, China
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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.
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Zheng Y, Hou L, Wang XL, Zhao CG, Du Y. A review of nephrotic syndrome and atopic diseases in children. Transl Androl Urol 2021; 10:475-482. [PMID: 33532335 PMCID: PMC7844495 DOI: 10.21037/tau-20-665] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Pediatric nephrotic syndrome (NS) is a common and recurrent glomerular disease in childhood. Furthermore, 50–70% of children with NS have increased total IgE in peripheral blood and a variety of clinical manifestations of atopic diseases. Hence, NS has many similarities with atopic diseases. However, no study has revealed a clear link between these two diseases. The present review discusses the correlation between pediatric NS and atopic diseases in children from three aspects: pathogenesis, cytokine change, and treatment. There are similar changes in T cells in terms of pathogenesis, with Th1/Th2 dysfunction and Treg cell function downregulation. Cytokine changes are similar and manifest as an increase in Th2 cytokines, TNF-α and TGF-β1, and a decrease in IL-10. Glucocorticoids, immunosuppressants and biological agents are used for the treatment of these two diseases. Therefore, it was speculated that NS and atopic diseases may be the same kind of disease, have a similar pathogenesis, and only exhibit different clinical manifestations due to different affected parts of the disease.
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Affiliation(s)
- Yue Zheng
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ling Hou
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiu-Li Wang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Cheng-Guang Zhao
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yue Du
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
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12
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Stasi A, Castellano G, Ranieri E, Infante B, Stallone G, Gesualdo L, Netti GS. SARS-CoV-2 and Viral Sepsis: Immune Dysfunction and Implications in Kidney Failure. J Clin Med 2020; 9:E4057. [PMID: 33334050 PMCID: PMC7765555 DOI: 10.3390/jcm9124057] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/04/2020] [Accepted: 12/08/2020] [Indexed: 01/10/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), first emerged in Wuhan, China. The clinical manifestations of patients infected with COVID-19 include fever, cough, and dyspnea, up to acute respiratory distress syndrome (ARDS) and acute cardiac injury. Thus, a lot of severe patients had to be admitted to intensive care units (ICU). The pathogenic mechanisms of SARS-CoV-2 infection are mediated by the binding of SARS-CoV-2 spikes to the human angiotensin-converting enzyme 2 (ACE-2) receptor. The overexpression of human ACE-2 is associated with the disease severity in SARS-CoV-2 infection, demonstrating that viral entry into cells is a pivotal step. Although the lung is the organ that is most commonly affected by SARS-CoV-2 infection, acute kidney injury (AKI), heart dysfunction and abdominal pain are the most commonly reported co-morbidities of COVID-19. The occurrence of AKI in COVID-19 patients might be explained by several mechanisms that include viral cytopathic effects in renal cells and the host hyperinflammatory response. In addition, kidney dysfunction could exacerbate the inflammatory response started in the lungs and might cause further renal impairment and multi-organ failure. Mounting recent evidence supports the involvement of cardiovascular complications and endothelial dysfunction in COVID-19 syndrome, in addition to respiratory disease. To date, there is no vaccine, and no specific antiviral medicine has been shown to be effective in preventing or treating COVID-19. The removal of pro-inflammatory cytokines and the shutdown of the cytokine storm could ameliorate the clinical outcome in severe COVID-19 cases. Therefore, several interventions that inhibit viral replication and the systemic inflammatory response could modulate the severity of the renal dysfunction and increase the probability of a favorable outcome.
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Affiliation(s)
- Alessandra Stasi
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (A.S.); (L.G.)
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy; (G.C.); (B.I.); (G.S.)
| | - Elena Ranieri
- Clinical Pathology, Department of Surgical and Medical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy;
| | - Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy; (G.C.); (B.I.); (G.S.)
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy; (G.C.); (B.I.); (G.S.)
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (A.S.); (L.G.)
| | - Giuseppe Stefano Netti
- Clinical Pathology, Department of Surgical and Medical Sciences, University of Foggia, Viale Luigi Pinto, 71122 Foggia, Italy;
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13
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Chen P, Chen Y, Jiang M, Mo Y, Ying H, Tang X, Zhang J. Usefulness of the cytokines expression of Th1/Th2/Th17 and urinary CD80 excretion in adult-onset minimal change disease. PeerJ 2020; 8:e9854. [PMID: 33194357 PMCID: PMC7485503 DOI: 10.7717/peerj.9854] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/11/2020] [Indexed: 12/16/2022] Open
Abstract
Background Minimal change disease (MCD) is a common form of nephrotic syndrome in adults. However, the molecular mechanism underlying the pathogenesis of MCD remains incompletely understood. In this study, we aimed to investigate the role of the cytokines expression of Th1/Th2/Th17 and urinary CD80 excretion in adult-onset MCD patients. Methods The lymphocyte subsets, 34 cytokine levels of Th1/Th2/Th17, serum and urine concentrations of CD80, and expression of CD80 in glomeruli were analyzed in 28 cases (15 males and 13 females; average age: 34.1 years, age range: 18–56 years), including 10 patients with MCD in relapse, nine patients with MCD in remission and nine healthy controls. Results There was no significant difference of CD3+CD4+ cells proportion among patients with MCD in relapse, MCD in remission and healthy controls (P = 0.802). The cytokine levels of GM-CSF and tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) in patients with MCD in relapse increased 1.5 times higher than those in remission. An evident increase in the excretion of urinary CD80 was found in patients with relapsed MCD compared with those in remission (598.4 ± 115.8 vs 81.78 ± 7.04 ng/g creatinine, P < 0.001) and healthy controls (598.4 ± 115.8 vs 67.44 ± 8.94 ng/g creatinine, P < 0.001). CD80 expression was observed in podocyte of MCD patient in relapse by immunofluorescence technique. Conclusions The cytokines GM-CSF and TRANCE are increased and the urinary CD80 levels are elevated in adult-onset MCD patients in relapse, indicating a disorder of Th1/Th2/Th17 balance and that the elevated excretion of CD80 may underlie the pathogenesis and development of adult-onset MCD.
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Affiliation(s)
- Ping Chen
- Department of Nephrology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Department of Nephrology, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Yan Chen
- Department of Physical Examination, Ningbo First hospital, Ningbo, Zhejiang, China
| | - Maoqing Jiang
- Department of Nuclear Medicine, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Yijun Mo
- Department of Laboratory Medicine, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Huanhuan Ying
- Department of Laboratory Medicine, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Xun Tang
- Department of Nephrology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Jun Zhang
- Department of Nephrology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China
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tRNA-Derived Fragments in Podocytes with Adriamycin-Induced Injury Reveal the Potential Mechanism of Idiopathic Nephrotic Syndrome. BIOMED RESEARCH INTERNATIONAL 2020; 2020:7826763. [PMID: 32685525 PMCID: PMC7330628 DOI: 10.1155/2020/7826763] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/12/2020] [Accepted: 05/29/2020] [Indexed: 11/17/2022]
Abstract
Idiopathic nephrotic syndrome (INS) is a disease involving injury to podocytes in the glomerular filtration barrier, and its specific causes have not been elucidated. Transfer RNA-derived fragments (tRFs), products of precise tRNA cleavage, have been indicated to play critical roles in various diseases. Currently, there is no relevant research on the role of tRFs in INS. This study intends to explore the changes in and importance of tRFs during podocyte injury in vitro and to further analyze the potential mechanism of INS. Differentially expressed tRFs in the adriamycin-treated group were identified by high-throughput sequencing and further verified by quantitative RT-PCR. In total, 203 tRFs with significant differential expression were identified, namely, 102 upregulated tRFs and 101 downregulated tRFs (q < 0.05, ∣log2FC | ≥2). In particular, AS-tDR-008924, AS-tDR-011690, tDR-003634, AS-tDR-013354, tDR-011031, AS-tDR-001008, and AS-tDR-007319 were predicted to be involved in podocyte injury by targeting the Gpr, Wnt, Rac1, and other genes. Furthermore, gene ontology analysis showed that these differential tRFs were strongly associated with podocyte injury processes such as protein binding, cell adhesion, synapses, the actin cytoskeleton, and insulin-activate receptor activity. KEGG pathway analysis predicted that they participated in the PI3K-Akt signaling pathway, Wnt signaling pathway, and Ras signaling pathway. It was reported that these pathways contribute to podocyte injury. In conclusion, our study revealed that changes in the expression levels of tRFs might be involved in INS. Seven of the differentially expressed tRFs might play important roles in the process of podocyte injury and are worthy of further study.
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15
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Hu T, Wang M, Chen W, Zhao J, Xiong J. The clinical characteristic and outcome of skin and soft tissue infection in immunosuppressive patients with nephrotic syndrome. Clin Exp Nephrol 2020; 24:779-788. [PMID: 32342290 DOI: 10.1007/s10157-020-01893-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 04/16/2020] [Indexed: 11/28/2022]
Abstract
OBJECTIVE Skin and soft tissue infection (SSTI) is the most common of infectious diseases with high morbidity and mortality. However, the clinical characteristics of SSTI in patients with nephrotic syndrome (NS), especially in those patients who received immunosuppressive therapy, are still lacking. The present study was conducted to investigate the clinical characteristics and outcomes of SSTI in patients with NS. METHODS A retrospective study was carried out among the patients diagnosed with NS and SSTI, who have priorly received or currently have been receiving immunosuppressive therapy between April 2011 and January 2019; the clinical profile included patient's baseline characteristics, clinical presentation, microbiological findings, treatment, and prognosis. RESULTS A total of 70 patients were analyzed. Results showed that more than half of the patients were under 35 years old, and moderate infection was the most common type of SSTI. Leg and cellulitis were the most common site of lesion and the typical clinical manifestation of SSTI, respectively. Patients in the severe infection group have a higher level of procalcitonin (PCT) and C-reactive protein (CRP), while a lower level of albumin, CD4+ T and CD8+ T cell count. Moreover, the gram-negative bacteria were the primary pathogens of SSTI in patients with NS, and Klebsiella pneumoniae were the most frequent strains isolated from those patients. Besides, patients in the mild and moderate infection groups experienced a better outcome. CONCLUSIONS Patients with NS and SSTI usually showed a satisfying outcome with proper anti-infection treatment, but severe SSTI can be life-threatening.
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Affiliation(s)
- Tianyu Hu
- Department of Hospital Infection Control, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, People's Republic of China
| | - Min Wang
- Department of Otorhinolaryngology and Head-Neck Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, People's Republic of China
| | - Wei Chen
- Department of Hospital Infection Control, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, People's Republic of China
| | - Jinghong Zhao
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Kidney Center of PLA, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, People's Republic of China
| | - Jiachuan Xiong
- Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Kidney Center of PLA, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, 400037, People's Republic of China.
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16
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Dong J, Jiang Z, Ma G. Hsp90 inhibition aggravates adriamycin-induced podocyte injury through intrinsic apoptosis pathway. Exp Cell Res 2020; 390:111928. [PMID: 32156599 DOI: 10.1016/j.yexcr.2020.111928] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 02/09/2020] [Accepted: 02/25/2020] [Indexed: 12/14/2022]
Abstract
Podocyte injury leads to impaired filtration barrier function of the kidney that underlies the pathophysiology of idiopathic nephrotic syndrome (INS), the most common NS occurring in children. The heat shock protein 90 (Hsp90) is involved in the regulation of apoptosis in a variety of cell types, however, little is known about its role in podocytes and whether it associated with NS. Here, we show that Hsp90 is upregulated in glomeruli podocytes from mice with adriamycin (ADR)-induced nephropathy, and that it is also upregulated in an immortalized podocyte cell line treated with ADR in vitro, together suggesting an association of Hsp90 upregulation in podocytes with NS pathogenesis. Functionally, Hsp90 inhibition with PU-H71 aggravates ADR-induced podocyte apoptosis and worsens the impairment of filtration barrier function. Mechanistically, Hsp90 inhibition with PU-H71 enhances the activation of intrinsic apoptotic pathway, and moreover, blockade of podocyte apoptosis with zVAD-fmk (aVAD), a pan-caspase inhibitor, abrogates effects of Hsp90 inhibition on filtration barrier function of ADR-treated podocytes, thus demonstrating that Hsp90 inhibition aggravates ADR-induced podocyte injury through intrinsic apoptosis pathway. In sum, this study reveals a detrimental role of Hsp90 inhibition in podocyte injury, which may offer it as a potential therapeutic target in NS therapy.
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Affiliation(s)
- Junyu Dong
- Department of Paediatrics, The First Affiliated Hospital of Henan University of Science & Technology, Luoyang, Henan, 471000, China
| | - Zhihong Jiang
- Department of Paediatrics, The First Affiliated Hospital of Henan University of Science & Technology, Luoyang, Henan, 471000, China.
| | - Guorui Ma
- Department of Paediatrics, The First Affiliated Hospital of Henan University of Science & Technology, Luoyang, Henan, 471000, China
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Prevalence of Asthma and Allergies and Risk of Relapse in Childhood Nephrotic Syndrome: Insight into Nephrotic Syndrome Cohort. J Pediatr 2019; 208:251-257.e1. [PMID: 30732999 DOI: 10.1016/j.jpeds.2018.12.048] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/21/2018] [Accepted: 12/19/2018] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To determine the lifetime prevalence of allergies in childhood nephrotic syndrome, the seasonality of presentation and relapses, and the impact of allergies on subsequent relapses. STUDY DESIGN In a longitudinal cohort of children with nephrotic syndrome (ages 1-18 years), assessment for allergic diseases was conducted using the validated and modified version of the International Study of Asthma and Allergies in Childhood questionnaire at enrollment. Outcomes included frequently relapsing nephrotic syndrome, relapse rates, and the relapse-free duration after initial steroid therapy. RESULTS Among 277 participants, the majority were male (65%) with a median age of 3.7 years (IQR 2.8-5.8) at presentation. A total of 64% reported lifetime allergies with 20% having asthma, 33% wheezing, 27% eczema, and 24% rhinitis. Over 3.3 years of follow-up, presence of asthma and allergies was not associated with frequently relapsing nephrotic syndrome (OR 1.20; 95% CI 0.60, 2.40), higher relapse rates (relative risk 0.95; 95% CI 0.71, 1.27), or risk of first relapse (hazard ratio 1.10; 95% CI 0.83, 1.47) compared with those with no history of allergic diseases. There was also no seasonal variation evident at initial presentation or frequency of relapses. CONCLUSIONS Two-thirds of children with nephrotic syndrome at presentation have allergic symptoms and asthma; however, neither are associated with an increased frequency of relapses.
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18
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Wei M, Wang PG. Desialylation in physiological and pathological processes: New target for diagnostic and therapeutic development. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2019; 162:25-57. [PMID: 30905454 DOI: 10.1016/bs.pmbts.2018.12.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Desialylation is a pivotal part of sialic acid metabolism, which initiates the catabolism of glycans by removing the terminal sialic acid residues on glycans, thereby modulating the structure and functions of glycans, glycoproteins, or glycolipids. The functions of sialic acids have been well recognized, whereas the function of desialylation process is underappreciated or largely ignored. However, accumulating evidence demonstrates that desialylation plays an important role in a variety of physiological and pathological processes. This chapter summarizes the current knowledge pertaining to desialylation in a variety of physiological and pathological processes, with a focus on the underlying molecular mechanisms. The potential of targeting desialylation process for diagnostic and therapeutic development is also discussed.
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Affiliation(s)
- Mohui Wei
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
| | - Peng George Wang
- Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, United States
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Zhai S, Zhao L, Zhang Y, Ma Q. Interleukin-7 stimulation inhibits nephrin activation and induces podocyte injury. Biochem Biophys Res Commun 2018; 507:100-105. [PMID: 30454893 DOI: 10.1016/j.bbrc.2018.10.173] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 10/28/2018] [Indexed: 12/26/2022]
Abstract
The glomerular podocytes control filtration barrier permeability in the kidney, and their disturbance underlies the pathogenesis of idiopathic nephrotic syndrome (INS), a kidney disease that predominantly occurs in children. In this study, we found that the interleukin-7 receptor (IL-7R) was induced in the glomeruli of adriamycin (ADR)-induced mouse nephropathy, a rodent model of nephrotic syndrome. In addition, IL-7R was also induced by ADR in mouse podocytes cultured in vitro. Functionally, we discovered that IL-7R activation through the stimulation of recombinant IL-7 induced apoptosis of podocytes, and moreover, IL-7 stimulation inhibited nephrin activation and caused actin cytoskeleton disorganization, indicating that IL-7 stimulation induces podocyte injury. Furthermore, IL-7 stimulation impaired the filtration barrier function of podocyte monolayer. Together, these results identify IL-7 and its receptor IL-7R as potential regulators of podocyte function, which might offer a novel therapeutic target in the treatment of INS.
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Affiliation(s)
- Shubo Zhai
- Department of Pediatric Nephropathy, The First Hospital of Jilin University, China
| | - Lengyue Zhao
- Department of Pediatric Nephropathy, The First Hospital of Jilin University, China
| | - Yan Zhang
- Department of Pediatric Nephropathy, The First Hospital of Jilin University, China
| | - Qingshan Ma
- Department of Pediatric Nephropathy, The First Hospital of Jilin University, China.
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Li T, Shi Y, Sun W, Wang H, Wang Q, Jiang Y. Increased PD-1 +CD154 + Tfh cells are possibly the most important functional subset of PD-1 + T follicular helper cells in adult patients with minimal change disease. Mol Immunol 2018; 94:98-106. [PMID: 29288900 DOI: 10.1016/j.molimm.2017.12.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 12/18/2017] [Accepted: 12/22/2017] [Indexed: 12/11/2022]
Abstract
T follicular helper (Tfh) cells, especially programmed cell death protein 1 (PD-1)+ Tfh cells, exert important functions in the normal immune response. The purpose of this study was to determine the frequency of different subsets of PD-1+ Tfh cells and their functional effects in adult patients with minimal change disease (MCD). The frequencies of circulating PD-1+, PD-1+CD154+, and PD-1+interleukin (IL)-21+ Tfh cells, and CD38+CD19+ and CD38+CD19+CD40+ B cells, as well as serum IL-2, IL-4, IL-17A, IL-6, IL-21, and interferon (IFN)-γ were significantly increased in the MCD patients compared with the healthy controls (HCs) (P < 0.05). However, no significant difference was found in PD-1+BCL-6+ or PD-1+ICOS+ Tfh cells. Furthermore, the percentages of PD-1+ Tfh and PD-1+CD154+ Tfh cells were negatively correlated with the estimated glomerular filtration rate (eGFR), but positively correlated with the 24-h urinary protein concentration and serum IL-21 level. The percentages of PD-1+ Tfh and PD-1+CD154+ Tfh cells were positively correlated with the percentages of CD38+ plasma cells and active CD38+CD40+ plasma cells, respectively. After an 8-12-week treatment with prednisolone, the percentages of PD-1+, PD-1+CD154+, and PD-1+IL-21+ Tfh cells as well as the serum level of IL-21 were significantly reduced; in contrast, the serum levels of IL-4 and IL-10 were increased (P < 0.05). We conclude that increased PD-1+CD154+ Tfh cells are possibly the most important functional subset of PD-1+ Tfh cells and may contribute towards the pathogenesis of MCD.
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Affiliation(s)
- Tao Li
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, 130021, China.
| | - Yunpeng Shi
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, 130021, China.
| | - Weixia Sun
- Department of Nephrology, The First Hospital of Jilin University, Changchun, 130021, China.
| | - Haifeng Wang
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, 130021, China.
| | - Quan Wang
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, 130021, China.
| | - Yanfang Jiang
- Genetic Diagnosis Center, The First Hospital of Jilin University, Changchun, 130021, China; Key Laboratory of Zoonoses Research, Ministry of Education, The First Hospital of Jilin University, Changchun, 130021, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou 225009, China.
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21
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Role of gut microbiota in idiopathic nephrotic syndrome in children. Med Hypotheses 2017; 108:35-37. [PMID: 29055396 DOI: 10.1016/j.mehy.2017.07.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 07/31/2017] [Indexed: 12/20/2022]
Abstract
Nephrotic syndrome characterized by heavy proteinuria and edema is the most common chronic kidney disease in children. It is classified into three categories, of which the idiopathic type accounts for the vast majority of cases. As indicated by the name, the etiology of idiopathic nephrotic syndrome remains unknown though it has been suggested that impaired T cell function is involved. Recently, evidence has mounted to suggest that dysfunction in regulatory T cells plays an important role in the development of allergic disease, a recognized comorbid condition for children with idiopathic nephrotic syndrome. It is known that regulatory T cells are mainly induced by short chain fatty acids produced by gut microbiota and that children with allergy are reported to have aberrant gut microbiota. On this basis, we hypothesize that an aberrant microbiota, i.e., dysbiosis in the gut resulting in defective induction of regulatory T cells, is also involved in the etiology of idiopathic nephrotic syndrome in children. Our hypothesis can be directly tested by metagenome analysis using bacterial DNA extracted from the feces of patients with idiopathic nephrotic syndrome. Indirect evidence could be obtained by epidemiological survey, such as a comparative study of the environmental factors influencing the initial colonization of gut microbiota between patients with idiopathic nephrotic syndrome and age-matched healthy children. Factors that may disrupt this colonization include a cesarean delivery, formula feeding, excessive use of antibiotics, or the introduction of inappropriate solid foods containing a high amount of saturated fat. Based on this hypothesis, we suggest it would be clinically worthwhile to study whether administration of probiotics composed of commensal bacteria known to efficiently induce regulatory T cells in vitro could control the exacerbation or relapse of INS.
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Tsuji S, Kimata T, Yamanouchi S, Kitao T, Kino J, Suruda C, Kaneko K. Regulatory T cells and CTLA-4 in idiopathic nephrotic syndrome. Pediatr Int 2017; 59:643-646. [PMID: 28544686 DOI: 10.1111/ped.13255] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 12/28/2016] [Accepted: 01/31/2017] [Indexed: 12/28/2022]
Abstract
The pathogenesis of idiopathic nephrotic syndrome (INS) remains unknown. Recently, it was postulated that suppression of regulatory T cells (Treg) leads to massive proteinuria in INS, although there is some controversy. Considering the important role of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in Treg-mediated immune suppression, the aim of this study was therefore to clarify the involvement of Treg and CTLA-4 in the pathogenesis of INS. Fifteen patients with INS were enrolled. Their blood was sampled twice, once at onset and once at remission induced by glucocorticoid. Although median Treg number was significantly lower at onset than in healthy children, it increased at remission. Similarly, serum CTLA-4 concentration significantly increased at remission compared with onset. Furthermore, a positive significant correlation was observed between Treg number and serum CTLA-4 level. This suggests that Treg and CTLA-4 are involved in the induction of remission in INS.
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Affiliation(s)
- Shoji Tsuji
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Takahisa Kimata
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | | | - Tetsuya Kitao
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Jiro Kino
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Chikushi Suruda
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Kazunari Kaneko
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
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Baris HE, Baris S, Karakoc-Aydiner E, Gokce I, Yildiz N, Cicekkoku D, Ogulur I, Ozen A, Alpay H, Barlan I. The effect of systemic corticosteroids on the innate and adaptive immune system in children with steroid responsive nephrotic syndrome. Eur J Pediatr 2016; 175:685-93. [PMID: 26833050 DOI: 10.1007/s00431-016-2694-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Revised: 01/08/2016] [Accepted: 01/18/2016] [Indexed: 11/25/2022]
Abstract
UNLABELLED The severity and duration of immunosuppression caused by corticosteroids (CSs) usage have not been extensively studied. We aimed to investigate the effects of CSs on the various compartments of immune system in relation to timing of initiation and persistence of therapy. Pediatric patients with idiopathic nephrotic syndrome (NS) treated with 2 mg/kg/day prednisolone and healthy control (HC) were enrolled. Blood samples were drawn for immunologic analyses at baseline and at the first and second weeks and first, second, and third months of CS therapy in addition to first and second weeks and first, second, and third months of discontinuation. Fourteen patients (M/F, 7/7) between 1 and 8 years old were evaluated. Untreated NS exhibited high absolute lymphocyte count (ALC)(p = 0.010), absolute CD3(+) T cells (p = 0.020) and absolute CD8(+) T cells (p = 0.006) compared to HC. Suppression in ALC was observed and nadir value was noted at first month of therapy compared to baseline (p = 0.002). The CD4(+) (p = 0.036) and CD8(+) T cell (p = 0.013) counts decreased significantly at the first week of treatment compared to baseline. While baseline B cell counts was indifferent from HC, gradually increased in 2 weeks of CS initiation and decreased during the treatment with a statistical significance compared to HC (p = 0.010). However, after cessation of CS, B cell counts continued to decline and found to be significantly different than baseline at first week (p = 0.008) and at third month (p = 0.040). CONCLUSION Apart from baseline lymphocyte subset changing observed in untreated NS patients, our data implies that T cells were suppressed very early in the CS treatment. Interestingly, depressed B cell counts were detected later but persisted even after CS cessation. Due to early decrease in T cells, it would be beneficial to assume the patients as immunosuppressed at the very beginning of CS treatment to avoid infections. WHAT IS KNOWN • Corticosteroids (CSs) are widely used for a variety of diseases including nephrotic syndrome, which is related with complex immune disturbance including T and B cells dysfunctions. • CSs induce neutrophilic leukocytosis concomitant with lymphopenia and eosinopenia leading to immunosupression. What is New: • T cell subsets and proliferation are susceptible to CSs more than B cells; however, the reversibility is faster with dose reduction in CS. • The change of B cells and B cell subtypes (CD27 (+) memory) shows prolonged effect of CSs on B cells which may alter antibody production even after 3 months of CSs cessation.
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Affiliation(s)
- Hatice Ezgi Baris
- Research and Training Hospital, Division of Pediatric Allergy and Immunology, Marmara University, Mimar Sinan Cad. No: 41, 34890, Istanbul, Turkiye
| | - Safa Baris
- Research and Training Hospital, Division of Pediatric Allergy and Immunology, Marmara University, Mimar Sinan Cad. No: 41, 34890, Istanbul, Turkiye.
| | - Elif Karakoc-Aydiner
- Research and Training Hospital, Division of Pediatric Allergy and Immunology, Marmara University, Mimar Sinan Cad. No: 41, 34890, Istanbul, Turkiye
| | - Ibrahim Gokce
- Research and Training Hospital, Division of Pediatric Nephrology, Marmara University, Istanbul, Turkiye
| | - Nurdan Yildiz
- Research and Training Hospital, Division of Pediatric Nephrology, Marmara University, Istanbul, Turkiye
| | - Dilek Cicekkoku
- Research and Training Hospital, Division of Pediatric Allergy and Immunology, Marmara University, Mimar Sinan Cad. No: 41, 34890, Istanbul, Turkiye
| | - Ismail Ogulur
- Research and Training Hospital, Division of Pediatric Allergy and Immunology, Marmara University, Mimar Sinan Cad. No: 41, 34890, Istanbul, Turkiye
| | - Ahmet Ozen
- Research and Training Hospital, Division of Pediatric Allergy and Immunology, Marmara University, Mimar Sinan Cad. No: 41, 34890, Istanbul, Turkiye
| | - Harika Alpay
- Research and Training Hospital, Division of Pediatric Nephrology, Marmara University, Istanbul, Turkiye
| | - Isil Barlan
- Research and Training Hospital, Division of Pediatric Allergy and Immunology, Marmara University, Mimar Sinan Cad. No: 41, 34890, Istanbul, Turkiye
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Teoh CW, Robinson LA, Noone D. Perspectives on edema in childhood nephrotic syndrome. Am J Physiol Renal Physiol 2015; 309:F575-82. [PMID: 26290369 DOI: 10.1152/ajprenal.00229.2015] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 08/11/2015] [Indexed: 12/21/2022] Open
Abstract
There have been two major theories surrounding the development of edema in nephrotic syndrome (NS), namely, the under- and overfill hypotheses. Edema is one of the cardinal features of NS and remains one of the principal reasons for admission of children to the hospital. Recently, the discovery that proteases in the glomerular filtrate of patients with NS are activating the epithelial sodium channel (ENaC), resulting in intrarenal salt retention and thereby contributing to edema, might suggest that targeting ENaC with amiloride might be a suitable strategy to manage the edema of NS. Other potential agents, particularly urearetics and aquaretics, might also prove useful in NS. Recent evidence also suggests that there may be other areas involved in salt storage, especially the skin, and it will be intriguing to study the implications of this in NS.
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Affiliation(s)
- Chia Wei Teoh
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Lisa A Robinson
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Damien Noone
- Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
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