|
1
|
Gu S, Shen T, Zhai Y, Yu J, Niu J, Xu W, Zeng Y, Shen Q, Xu H, Yang X. The efficacy and dynamic changes of immune function of rituximab with mycophenolate mofetil in the treatment of steroid-dependent /frequently relapsing nephrotic syndrome: a retrospective follow-up study. BMC Nephrol 2025; 26:186. [PMID: 40211202 PMCID: PMC11987447 DOI: 10.1186/s12882-025-04093-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 03/25/2025] [Indexed: 04/12/2025] Open
Abstract
INTRODUCTION Approximately 70%～90% of children with steroid-sensitive nephrotic syndrome (SSNS) will suffer from steroid dependency or frequent relapses, prompting the use of steroid-sparing agent. In this study, we investigate the efficacy and the characteristics of dynamic changes in immune function of two doses of rituximab (RTX) in the treatment of steroid-dependent/frequently relapsing nephrotic syndrome (SDNS /FRNS). METHOD Retrospective follow-up study was conducted in our hospital from June 2022 to September 2023. 7 children with SDNS /FRNS were allocated to intravenous 2 doses RTX (each dose 375mg/m2, 1 dose per week) and administered the standard oral dose of mycophenolate mofetil (MMF) (1000-1200/m2/d, divided into 2 doses) when B cells have recovered (≥ 5/ul). The study subjects after treatment were monitored for the efficacy and dynamic changes of immune function for 12 months. RESULT 7 children with SDNS/FRNS who were treated RTX with MMF and followed up for 12 months have no relapse. The rate of B cell depletion (< 5/ul) was 100% at 1 week after the second dose of RTX treatment, and the rate of B cell recovery was 100% at 5-12 months after the first dose of RTX treatment. There was no significant difference with T cell subsets (CD3, CD4, CD8, CD4/CD8) at each follow-up time points (all P > 0.05). The count of NK cells was significantly higher than that of other groups at 1 week after the second dose (P < 0.05). The IgM level at 1 week after the second dose was significantly lower than that before treatment and 1 week after the first dose (P < 0.05). There were no significant differences with IgA, IgG, C3 and C4 before treatment, 1 week after the first dose and 1 week after the second dose (all P > 0.05). CONCLUSION AND RECOMMENDATION Administering two doses of RTX along with the standard dose of MMF has been effective in maintaining remission for children with SDNS/FRNS. B cell depletion can be achieved one week after the second dose of RTX treatment. NK cell proliferation may play a role in B cell depletion, and early B cell depletion may suppress the production of IgM. These findings require further validation through additional clinical trials and basic research.
Collapse
Affiliation(s)
- Songlei Gu
- Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Zhenhai Road 10, Xiamen, Fujian, 361102, China
| | - Tong Shen
- Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Zhenhai Road 10, Xiamen, Fujian, 361102, China
| | - Yihui Zhai
- Department of Nephrology, Children's Hospital of Fudan University, Wanyuan Road 399, Shanghai, 201102, China
| | - Jie Yu
- Pediatrics Department, Nanping Zhenghe County General Hospital, Shuinan Middle Road 69, Nanping, 353600, China
| | - Jie Niu
- Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Zhenhai Road 10, Xiamen, Fujian, 361102, China
| | - Wenli Xu
- Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Zhenhai Road 10, Xiamen, Fujian, 361102, China
| | - Yugui Zeng
- Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Zhenhai Road 10, Xiamen, Fujian, 361102, China
| | - Qian Shen
- Department of Nephrology, Children's Hospital of Fudan University, Wanyuan Road 399, Shanghai, 201102, China
| | - Hong Xu
- Department of Nephrology, Children's Hospital of Fudan University, Wanyuan Road 399, Shanghai, 201102, China.
| | - Xiaoqing Yang
- Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Zhenhai Road 10, Xiamen, Fujian, 361102, China.
| |
Collapse
|
|
2
|
Ahmad A, Mallela SK, Ansari S, Alnukhali M, Ali M, Merscher S, Pollack A, Zeidan YH, Fornoni A, Marples B. Radiation-Induced Nephrotoxicity: Role of Sphingomyelin Phosphodiesterase Acid-like 3b. Int J Radiat Oncol Biol Phys 2025; 121:1271-1281. [PMID: 39667585 DOI: 10.1016/j.ijrobp.2024.11.105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 10/18/2024] [Accepted: 11/29/2024] [Indexed: 12/14/2024]
Abstract
PURPOSE Radiation nephropathy (RN) can be a significant late complication after radiation therapy (RT) for abdominal and paraspinal tumors. The mechanisms for the development of RN are thought to involve disruption of podocyte function, leading to podocyte cell death and, finally, impaired renal function. This study investigated the mechanistic role of sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) in regulating podocyte injury and renal function after irradiation. The aim of the study was to investigate the potential linkage between (1) RT-induced renal dysfunction and podocyte SMPDL3b expression and (2) RT-induced podocyte injury and expansion of the glomerular basement membrane (GBM). METHODS AND MATERIALS SMPDL3b wild-type, siSMPDL3b, and SMPDL3b-overexpressing podocytes were irradiated in cell culture, and cell death was assessed. SMPDL3b wild-type and podocyte-specific SMPDL3b knockout mice were treated with focal bilateral kidney X-irradiation (14 Gy, or 6 × 5 Gy), and podocyte apoptosis, renal function parameters, glomerular filtration rate, glomerular histology, and GBM ultrastructural changes via transmission electron microscopy were assessed. RESULTS Following RT treatment, a notable decrease in SMPDL3b expression was observed, accompanied by heightened levels of DNA damage, cytoskeletal alterations, and apoptotic events in cultured podocytes. SMPDL3b overexpression notably prevented DNA damage and apoptosis in cultured podocytes. Additionally, in vivo, RT exposure led to a significant decline in SMPDL3b expression, podocyte count, and renal function while concomitantly elevating GBM thickness, mesangial expansion, and renal fibrosis at the 20-week post-RT. Furthermore, in vivo, rituximab pretreatment before RT prevented SMPDL3b downregulation, podocyte loss, mesangial expansion, GBM expansion, and renal fibrosis and ultimately enhanced renal function post-RT. CONCLUSIONS Our findings collectively suggest a novel function for SMPDL3b in orchestrating the DNA damage response triggered by radiation. This study proposes that SMPDL3b exerts a regulatory influence on the repair of double-strand breaks within podocytes, consequently averting podocyte loss, GBM expansion, and the onset of RN.
Collapse
Affiliation(s)
- Anis Ahmad
- Department of Radiation Oncology, University of Miami, Sylvester Comprehensive Cancer Center/ Miller School of Medicine
| | - Shamroop Kumar Mallela
- Peggy and Harold Katz Family Drug Discovery Center and Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miami, Florida
| | - Saba Ansari
- Department of Radiation Oncology, University of Miami, Sylvester Comprehensive Cancer Center/ Miller School of Medicine
| | - Mohammed Alnukhali
- Department of Radiation Oncology, University of Miami, Sylvester Comprehensive Cancer Center/ Miller School of Medicine
| | - Misha Ali
- Department of Radiation Oncology, University of Miami, Sylvester Comprehensive Cancer Center/ Miller School of Medicine
| | - Sandra Merscher
- Peggy and Harold Katz Family Drug Discovery Center and Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miami, Florida
| | - Alan Pollack
- Department of Radiation Oncology, University of Miami, Sylvester Comprehensive Cancer Center/ Miller School of Medicine
| | - Youssef H Zeidan
- Department of Radiation Oncology, American University of Beirut, Beirut, Lebanon and Baptist Health, Lynn Cancer Institute, Boca Raton, Florida
| | - Alessia Fornoni
- Peggy and Harold Katz Family Drug Discovery Center and Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miami, Florida
| | - Brian Marples
- Department of Radiation Oncology, University of Miami, Sylvester Comprehensive Cancer Center/ Miller School of Medicine; Department of Radiation Oncology, University of Rochester, Rochester, New York.
| |
Collapse
|
|
3
|
Zhong A, Yu Y, Cao T, Wan Q, Xu R. Emerging role of Rituximab in adult minimal change disease: a narrative review of clinical evidence, biomarkers and future perspectives. BMC Nephrol 2025; 26:152. [PMID: 40140772 PMCID: PMC11938555 DOI: 10.1186/s12882-025-04086-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Accepted: 03/19/2025] [Indexed: 03/28/2025] Open
Abstract
Minimal change disease (MCD) represents a significant cause of nephrotic syndrome in adults, traditionally managed with corticosteroids despite substantial relapse rates. This review critically evaluates the emerging role of rituximab (RTX) in adult MCD management, synthesizing current evidence across multiple clinical scenarios. Recent studies demonstrate RTX's multifaceted efficacy, particularly in new-onset cases and steroid-dependent/frequently relapsing patients, with the discovery of anti-nephrin antibodies providing unprecedented insights into MCD pathogenesis. RTX's therapeutic mechanisms involve anti-nephrin antibody depletion, T-cell subset modulation, and direct podocyte protection, showing encouraging complete remission rates and substantially reduced relapse rates. While RTX offers a more favorable safety profile compared to long-term corticosteroid therapy, current evidence remains predominantly based on retrospective studies with limited sample sizes. Critical research priorities include large-scale prospective trials, standardization of treatment protocols, and further investigation of anti-nephrin antibodies as therapeutic targets. This review provides evidence-based insights for clinical decision-making while highlighting crucial areas for future investigation in RTX-based MCD management.
Collapse
Affiliation(s)
- Anni Zhong
- Department of Nephrology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, 3002 Sungang West Road, Shenzhen, Guangdong, 518035, China
| | - Yi Yu
- Department of Nephrology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, 3002 Sungang West Road, Shenzhen, Guangdong, 518035, China
| | - Tao Cao
- Department of Nephrology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, 3002 Sungang West Road, Shenzhen, Guangdong, 518035, China
| | - Qijun Wan
- Department of Nephrology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, 3002 Sungang West Road, Shenzhen, Guangdong, 518035, China
| | - Ricong Xu
- Department of Nephrology, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, 3002 Sungang West Road, Shenzhen, Guangdong, 518035, China.
| |
Collapse
|
|
4
|
He C, Peng W, Li S, Xu C, Chen X, Qin Y. ECHS1 as a Lipid Metabolism Biomarker for Pediatric Focal Segmental Glomerulosclerosis. PLoS One 2025; 20:e0319049. [PMID: 40063869 PMCID: PMC11893130 DOI: 10.1371/journal.pone.0319049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Accepted: 01/26/2025] [Indexed: 05/13/2025] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome and often leads to end-stage renal disease. However, the underlying pathophysiological mechanisms that contribute to disease progression require further investigation to establish appropriate therapeutic targets and biomarkers. This study aimed to clarify the molecular mechanisms underlying FSGS by focusing on differentially expressed genes (DEGs) and lipid metabolism-related genes (LMRGs). We utilized the GSE69814, GSE129973, and GSE121233 datasets, which comprise glomerular transcriptomes from patients with FSGS, minimal change disease (MCD), and unaffected kidney tissues. We identified 2,459 DEGs from the GSE69814 dataset and 982 DEGs from the GSE129973 dataset. These DEGs intersected 1,450 LMRGs, resulting in 56 differentially expressed LMRGs (DELMRGs). Enrichment analysis revealed that these DELMRGs were primarily involved in fatty acid metabolic processes; localized in microbodies, peroxisomes, and mitochondrial matrices; and exhibited oxidoreductase activity. Protein-protein interaction networks were constructed using Cytoscape, and five hub DELMRGs (enoyl-CoA hydratase, short chain 1 [ECHS1], EHHADH, IDH1, SUCLG1, and ALDH3A2) were identified using multiple algorithms. We assessed the diagnostic performance using receiver operating characteristic curves and expression levels from the GSE121233 dataset, and found that ECHS1 and ALDH3A2 showed strong diagnostic potential. Immunohistochemical verification of clinical specimens from children confirmed significant expression of ECHS1 in FSGS compared with that in normal and MCD tissues. This study highlights ECHS1 as a potential biomarker for pediatric FSGS, suggesting a potential role in early diagnosis or personalized treatment, offering insights into its pathogenesis and paving the way for targeted therapeutic strategies.
Collapse
Affiliation(s)
- Chao He
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University
- The First Affiliated Hospital, Department of Pediatrics, Hengyang Medical School, University of South China
| | - Wei Peng
- Department of Pediatrics, People’s Hospital of Ningxiang City
| | - Sheng Li
- The First Affiliated Hospital, Department of Pediatrics, Hengyang Medical School, University of South China
| | - Can Xu
- The First Affiliated Hospital, Department of Cardiology, Institute of Cardiovascular Disease, Hengyang Medical School, University of South China
| | - Xiuping Chen
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University
| | - Yuanhan Qin
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University
| |
Collapse
|
|
5
|
Yun AN, Rogers AW, Krisl JC, Kagan A, Adrogue HE, Khan AJ, Khairallah P, Yi SG, Hobeika MJ, Gaber L, Truong L, Podder H, Gaber AO, Knight RJ. Impact of Therapeutic Plasma Exchange and Rituximab for Prevention of Idiopathic Focal Segmental Glomerulosclerosis Recurrence Post-Kidney Transplantation. Transplant Direct 2025; 11:e1769. [PMID: 40034162 PMCID: PMC11875572 DOI: 10.1097/txd.0000000000001769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 12/26/2024] [Indexed: 03/05/2025] Open
Abstract
Background Focal segmental glomerulosclerosis (FSGS) recurs after kidney transplantation (KT) in 30%-50% of recipients. Recurrence is associated with early graft loss in up to 60% of cases. This study aimed to assess the efficacy of therapeutic plasma exchange (TPE) combined with rituximab (RTX) in preventing early FSGS recurrence within 1 y post-KT. Methods This single-center, retrospective cohort study included patients receiving KT for idiopathic FSGS between June 2013 and August 2021. In May 2016, a preventative FSGS protocol was implemented where KT recipients with idiopathic FSGS received perioperative sessions of TPE followed by a dose of RTX with or without IVIG. The incidence of recurrent FSGS within the first year posttransplantation was assessed between the FSGS protocol cohort versus the historical group of patients who did not undergo prophylactic treatment. Results A total of 65 patients received KT for idiopathic FSGS during the study period. Forty patients were included in the FSGS protocol cohort and 25 in the control cohort. When assessing clinical recurrence with proteinuria, there were significantly fewer cases in the FSGS protocol cohort versus the control cohort, 1 versus 5 patients (3% versus 20%, P = 0.03). There were no instances of death-censored graft loss at 1 y in the protocol cohort versus 2 cases in the control cohort (0% versus 8%, P = 0.14). Conclusions TPE combined with RTX may prevent early FSGS recurrence without significant rates of infection.
Collapse
Affiliation(s)
- Allison N. Yun
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX
| | - Alex W. Rogers
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX
| | - Jill C. Krisl
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX
| | - Anna Kagan
- Division of Nephrology, Department of Internal Medicine, Houston Methodist Hospital, Houston, TX
| | - Horacio E. Adrogue
- Division of Nephrology, Department of Internal Medicine, Houston Methodist Hospital, Houston, TX
| | - Abdul J. Khan
- Division of Nephrology, Department of Internal Medicine, Houston Methodist Hospital, Houston, TX
| | | | - Stephanie G. Yi
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- J.C. Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Mark J. Hobeika
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- J.C. Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Lillian Gaber
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX
- Department of Pathology, Weill Cornell Medical College, New York, NY
| | - Luan Truong
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX
- Department of Pathology and Medicine, Baylor College of Medicine, Houston, TX
| | - Hemangshu Podder
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- J.C. Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Ahmed O. Gaber
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- J.C. Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Richard J. Knight
- Department of Surgery, Houston Methodist Hospital, Houston, TX
- J.C. Walter Jr. Center for Transplantation, Houston Methodist Hospital, Houston, TX
- Department of Surgery, Weill Cornell Medical College, New York, NY
| |
Collapse
|
|
6
|
Uro-Coste C, Lambert C, Audard V, Couzi L, Caillard S, Büchler M, Del Bello A, Malvezzi P, Pernin V, Colosio C, Mesnard L, Bertrand D, Martinez F, Ducloux D, Poulain C, Thierry A, Danthu C, Greze C, Lanaret C, Moal V, Hertig A, Dantal J, Legendre C, Chatelet V, Sicard A, Gosset C, Maillard N, Duveau A, Petit C, Kamar N, Heng AE, Anglicheau D, Garrouste C. Prophylactic treatment of FSGS recurrence in patients who relapsed on a previous kidney graft. Nephrol Dial Transplant 2025; 40:475-483. [PMID: 38794882 PMCID: PMC11879060 DOI: 10.1093/ndt/gfae108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation and is classically associated with a significant decrease in graft survival. A major risk factor is a prior history of FSGS recurrence on a previous graft. This analysis reports the impact of a prophylactic treatment of FSGS recurrence in very high-risk patients who experienced a recurrence on a previous graft. METHODS We performed a retrospective multicentre observational study in 25 French transplantation centres. The inclusion criteria were patients aged more than 18 years who had undergone kidney transplant between 31 December 2004 and 31 December 2020, and who had a history of FSGS recurrence on a previous graft. RESULTS We identified 66 patients: 40 received prophylactic treatment (PT+), including intravenous cyclosporine and/or rituximab and/or plasmapheresis, and 26 did not receive any prophylactic treatment (PT-). The time to progression to end-stage kidney disease was similar between groups. The PT+ group was younger at FSGS diagnosis and at the time of kidney retransplantation and lost their previous graft faster. The overall recurrence rate was 72.7% (76.9% in the PT- group and 70.0% in the PT+ group, P = .54). At least partial remission was achieved in 87.5% of patients. The 5-year graft survival was 67.7% [95% confidence interval (CI) 53.4%-78.4%]: 65.1% (95% CI 48.7%-77.4%) in patients with FSGS recurrence vs 77.3% (95% CI 43.8%-92.3%) in patients without recurrence (P = .48). CONCLUSION Our study suggests that prophylactic treatment should not be used routinely in patients receiving a second transplantation after recurrence of FSGS on a previous graft. The recurrence rate is high regardless of the use of prophylactic treatment. However, the 5-year graft survival remains satisfactory.
Collapse
Affiliation(s)
| | - Céline Lambert
- Unité de Biostatistiques, DRCI, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Vincent Audard
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation Centre de Référence Maladie Rare « Syndrome Néphrotique Idiopathique », Hôpitaux Universitaires Henri-Mondor, Univ Paris Est Créteil, INSERM, IMRB, Créteil, France
| | - Lionel Couzi
- Service de Néphrologie, Transplantation, Dialyse et Aphérèses, CHU de Bordeaux, Bordeaux, France
| | - Sophie Caillard
- Service de Néphrologie, University Hospital, Strasbourg, France
| | - Matthias Büchler
- Service de Néphrologie et Immunologie Clinique, CHRU de Tours, Tours, France
| | - Arnaud Del Bello
- Département de Néphrologie et Transplantation d'Organes, CHU Toulouse, INSERM U1043, IFR–BMT, Université Paul Sabatier, Toulouse, France
| | - Paolo Malvezzi
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
| | - Vincent Pernin
- Service de Néphrologie, Dialyse et Transplantation, Hôpital Lapeyronie, CHU Montpellier, Montpellier, France
| | | | - Laurent Mesnard
- Assistance Publique – Hôpitaux de Paris, Soins Intensifs Néphrologiques et Rein Aigu, APHP Sorbonne Université, Hôpital Tenon, Paris, France
| | | | - Frank Martinez
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Didier Ducloux
- Service de Néphrologie, Dialyse et Transplantation, CHU Besançon, Besançon, France
| | - Coralie Poulain
- Service de Néphrologie-Médecine Interne-Dialyse-Transplantation, CHU d'Amiens, Amiens, France
| | - Antoine Thierry
- Service de Néphrologie-Hémodialyse-Transplantation Rénale, CHU de Poitiers, Poitiers, France
| | - Clément Danthu
- Service de Néphrologie, Dialyse et Transplantation, CHU Limoges, Limoges, France
| | - Clarisse Greze
- Service de Néphrologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | | | - Valérie Moal
- Aix Marseille Université, Assistance Publique Hôpitaux de Marseille, Hôpital Conception, Centre de Néphrologie et Transplantation Rénale, Marseille, France
| | | | - Jacques Dantal
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie Clinique, CHU Nantes, Nantes, France
| | - Christophe Legendre
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Valérie Chatelet
- Centre Universitaire des Maladies Rénales, Centre Hospitalier Universitaire de Caen, Caen, France
| | - Antoine Sicard
- Service de Néphrologie, Dialyse et Transplantation, CHU Nice, Nice, France
| | - Clément Gosset
- Service de Néphrologie, Dialyse et Transplantation, CHU Nice, Nice, France
| | - Nicolas Maillard
- Service de Néphrologie et Transplantation, CHU Saint-Etienne, Saint-Etienne, France
| | - Agnès Duveau
- Service de Néphrologie, CHU Angers, Angers, France
| | - Clémence Petit
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie Clinique, CHU Nantes, Nantes, France
| | - Nassim Kamar
- Département de Néphrologie et Transplantation d'Organes, CHU Toulouse, INSERM U1043, IFR–BMT, Université Paul Sabatier, Toulouse, France
| | | | - Dany Anglicheau
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Cyril Garrouste
- Service de Néphrologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
| |
Collapse
|
|
7
|
Zhu Y, Xu G. Advances in Focal Segmental Glomerulosclerosis Treatment From the Perspective of the Newest Mechanisms of Podocyte Injury. Drug Des Devel Ther 2025; 19:857-875. [PMID: 39935575 PMCID: PMC11812565 DOI: 10.2147/dddt.s498457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 12/19/2024] [Indexed: 02/13/2025] Open
Abstract
Podocyte injury was widely recognized as a fundamental mechanism driving the progression of focal segmental glomerulosclerosis (FSGS). Recent research has therefore focused on the development of targeted therapies aimed at disrupting specific pathogenic signaling cascades within podocytes, resulting in noteworthy advancements. The role of mechanisms such as alterations in the actin cytoskeleton, oxidative stress, mitochondrial dysfunction, and inadequate autophagy within the microenvironment of podocyte injury have garnered increasing attention. Corresponding targeted medications such as Abatacept, chemokine receptor (CCR) inhibitors, CDDO-Im (2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide), adenosine monophosphate-activated protein kinase (AMPK) activators, and Adalimumab are currently under investigation. Notably, some medications such as Rituximab and Sparsentan, may simultaneously target multiple downstream mechanisms, Furthermore, exploring molecular strategies for established medications and developing novel treatments guided by biomarkers such as Anti-CD40 antibody, blood microRNA, urinary microRNA, and tumor necrosis factor-alpha (TNF-α) may provide additional therapeutic avenues for patients with FSGS.
Collapse
Affiliation(s)
- Yan Zhu
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
- Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
| | - Gaosi Xu
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
- Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang City, Jiangxi Province, People’s Republic of China
| |
Collapse
|
|
8
|
Guaragna MS, Casimiro FMS, Varela P, de S Feltran L, Watanabe A, Neves PDMM, Pesquero JB, Belangero VMS, Nogueira PCK, Onuchic LF. Past and future in vitro and in vivo approaches toward circulating factors and biomarkers in idiopathic nephrotic syndrome. Pediatr Nephrol 2025:10.1007/s00467-024-06643-8. [PMID: 39883133 DOI: 10.1007/s00467-024-06643-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 11/26/2024] [Accepted: 12/09/2024] [Indexed: 01/31/2025]
Abstract
Predicting the risks of progression to chronic kidney disease (CKD) stage 5 in idiopathic nephrotic syndrome (NS) and recurrence of the disease (rNS) following kidney transplantation (KT) is a key assessment to provide essential management information. NS has been categorized etiologically as genetic and immune-based. A genetic cause can be identified in ~ 30% of children with steroid-resistant NS (SRNS), a finding associated with a very low risk of rNS following KT. In immune-based NS, clinical overlap is observed among steroid-sensitive NS, secondary-resistant NS, and SRNS not associated with disease-causing genetic variants (non-monogenic SRNS). While ~ 50% of SRNS patients with no identified monogenic disease respond to intensified immunosuppressive treatments, the ones that do not respond to this therapy have a high risk of progression to CKD stage 5 and post-KT rNS. Secondary-resistant patients who progress to CKD stage 5 display the highest risk of post-KT rNS. The proposed shared underlying mechanism of the immune-based NS associated with post-KT rNS is based on a systemic circulating factor (CF) that affects glomerular permeability by inducing foot process effacement and focal segmental glomerulosclerosis. However, identifying patients without a detected genetic form who will recur post-KT is a major challenge. Extensive efforts, therefore, have been made to identify CFs and biomarkers potentially capable of predicting the risk of progression to CKD stage 5 and post-KT rNS. This review discusses the in vitro and in vivo approaches employed to date to identify and characterize potential CFs and CF-induced biomarkers of recurrent NS and offers an assessment of their potential to improve outcomes of KT in this patient population.
Collapse
Affiliation(s)
- Mara S Guaragna
- Department of Medical Genetics and Genomic Medicine, School of Medical Sciences, State University of Campinas, Campinas, Brazil
- Center for Molecular Biology and Genetic Engineering, State University of Campinas, Campinas, Brazil
| | - Fernanda M S Casimiro
- Center for Diagnosis and Research On Genetic Diseases, Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil
| | - Patrícia Varela
- Center for Diagnosis and Research On Genetic Diseases, Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Luciana de S Feltran
- Division of Pediatric Kidney Transplantation, São Paulo Samaritan Hospital, São Paulo, Brazil
| | - Andreia Watanabe
- Department of Pediatrics, University of São Paulo School of Medicine, São Paulo, Brazil
- Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Precil D M M Neves
- Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
- Division of Nephrology, University of São Paulo School of Medicine, Avenida Dr. Arnaldo, 455 - Sala 4304, São Paulo, SP, 01246-903, Brazil
| | - João B Pesquero
- Center for Diagnosis and Research On Genetic Diseases, Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil
| | - Vera M S Belangero
- Department of Pediatrics, School of Medical Sciences, State University of Campinas, Campinas, Brazil
| | - Paulo C K Nogueira
- Division of Pediatric Kidney Transplantation, São Paulo Samaritan Hospital, São Paulo, Brazil
- Department of Pediatric Nephrology, São Paulo Federal University, São Paulo, Brazil
| | - Luiz F Onuchic
- Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
- Division of Nephrology, University of São Paulo School of Medicine, Avenida Dr. Arnaldo, 455 - Sala 4304, São Paulo, SP, 01246-903, Brazil.
| |
Collapse
|
|
9
|
Hackl A, Weber LT. The Ca 2+-actin-cytoskeleton axis in podocytes is an important, non-immunologic target of immunosuppressive therapy in proteinuric kidney diseases. Pediatr Nephrol 2025:10.1007/s00467-025-06670-z. [PMID: 39856247 DOI: 10.1007/s00467-025-06670-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 12/19/2024] [Accepted: 12/19/2024] [Indexed: 01/27/2025]
Abstract
The integrity of the filtration barrier of the kidney relies on the proper composition of podocyte interdigitating foot processes. Their architecture is supported by a complex actin-cytoskeleton. Following podocyte stress or injury, podocytes encounter structural changes, including rearrangement of the actin network and subsequent effacement of the foot processes. Immunosuppressive drugs, which are currently used as treatment in proteinuric kidney diseases, have been shown to exert not only immune-mediated effects. This review will focus on the direct effects of glucocorticoids, cyclosporine A, tacrolimus, mycophenolate mofetil, and rituximab on podocytes by regulation of Ca2+ ion channels and consecutive downstream signaling which prevent cytoskeletal rearrangements and ultimately proteinuria. In addition, the efficacy of these drugs in genetic nephrotic syndrome will be discussed.
Collapse
Affiliation(s)
- Agnes Hackl
- Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Street 62, 50937, Cologne, Germany.
| | - Lutz T Weber
- Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Street 62, 50937, Cologne, Germany
| |
Collapse
|
|
10
|
Zhang X, Jin Y, Liu F, Li Q, Xie Y, Huang G, chen J, He X, He S, Fu H, Wang J, Shen H, Mao J. Rituximab as a first-line therapy in children with new-onset idiopathic nephrotic syndrome. Clin Kidney J 2025; 18:sfae348. [PMID: 39811259 PMCID: PMC11730066 DOI: 10.1093/ckj/sfae348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Indexed: 01/16/2025] Open
Abstract
Background Idiopathic nephrotic syndrome (INS) in children, commonly treated with steroids, poses challenges due to associated side effects. Rituximab, known for its efficacy in reducing relapse frequency in difficult-to-treat cases, emerges a potential first-line therapy for pediatric new-onset INS. Method This is a single-center, retrospective, observational study to evaluate the efficacy and safety of rituximab as a first-line therapy for pediatric INS. The complete treatment strategy was weekly injections at a dose of 375 mg/m2 for four doses. Children with new-onset INS who received rituximab as a first-line monotherapy from 1 January 2022 to 31 December 2023 were included and followed until 31 May 2024. Results Seventeen patients (median age at diagnosis 4.8 years) were included. Twelve patients achieved complete remission within a median time of 19 days. Over a follow-up period ranging from 41 to 112 weeks, 11 patients maintained remission even after B-cell reconstitution, with one patient experiencing a relapse at 85 weeks. Three patients, who presented with hematuria, hypocomplementemia or renal injury at initial diagnosis, exhibited resistance to rituximab. No severe adverse events were noted. Conclusion Rituximab may be an effective and safe option as a first-line therapy for inducing and maintaining remission in newly diagnosed INS.
Collapse
Affiliation(s)
- Xiaojing Zhang
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Yanyan Jin
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Fei Liu
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Qiuyu Li
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Yi Xie
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Guoping Huang
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Junyi chen
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Xue He
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Siyi He
- Department of Pediatrics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Haidong Fu
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Jingjing Wang
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Huijun Shen
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| | - Jianhua Mao
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China
| |
Collapse
|
|
11
|
Wang M, Yao F, Chen N, Wu T, Yan J, Du L, Zeng S, Du C. The advance of single cell transcriptome to study kidney immune cells in diabetic kidney disease. BMC Nephrol 2024; 25:412. [PMID: 39550562 PMCID: PMC11568691 DOI: 10.1186/s12882-024-03853-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 11/05/2024] [Indexed: 11/18/2024] Open
Abstract
Diabetic kidney disease (DKD) is a prevalent microvascular complication of diabetes mellitus and a primary cause of end-stage renal disease (ESRD). Increasing studies suggest that immune cells are involved in regulating renal inflammation, which contributes to the progression of DKD. Compared with conventional methods, single-cell sequencing technology is more developed technique that has advantages in resolving cellular heterogeneity, parallel multi-omics studies, and discovering new cell types. ScRNA-seq helps researchers to analyze specifically gene expressions, signaling pathways, intercellular communication as well as their regulations in various immune cells of kidney biopsy and urine samples. It is still challenging to investigate the function of each cell type in the pathophysiology of kidney due to its complex and heterogeneous structure and function. Here, we discuss the application of single-cell transcriptomics in the field of DKD and highlight several recent studies that explore the important role of immune cells including macrophage, T cells, B cells etc. in DKD through scRNA-seq analyses. Through combing the researches of scRNA-seq on immune cells in DKD, this review provides novel perspectives on the pathogenesis and immune therapeutic strategy for DKD.
Collapse
Affiliation(s)
- Mengjia Wang
- Department of Pathology, Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, 050017, China
| | - Fang Yao
- Department of Pathology, Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, 050017, China
- Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China
| | - Ning Chen
- Department of Pathology, The First Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ting Wu
- Department of Pathology, Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, 050017, China
- Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China
| | - Jiaxin Yan
- Department of Pathology, Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, 050017, China
- Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China
| | - Linshan Du
- Department of Pathology, Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, 050017, China
| | - Shijie Zeng
- Department of Pathology, Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, 050017, China
| | - Chunyang Du
- Department of Pathology, Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, 050017, China.
- Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China.
| |
Collapse
|
|
12
|
Chebotareva NV, Charionovskaya EA, Biryukova EA, Vinogradov AA, Alentov II, Sergeeva NS, Kononikhin AS, Nikolaev EN, Moiseev SV. Increased levels of antibodies to synaptopodin and annexin 1 in patients with primary podocytopathies. FRONTIERS IN NEPHROLOGY 2024; 4:1471078. [PMID: 39544697 PMCID: PMC11560892 DOI: 10.3389/fneph.2024.1471078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/07/2024] [Indexed: 11/17/2024]
Abstract
Introduction Circulating anti-podocyte antibodies have been proposed as potential factors contributing to increased permeability in primary podocytopathies, such as Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS). The aim of the study was to to assess the levels of antibodies targeting synaptopodin and annexin 1 in the blood serum of patients diagnosed with nephrotic syndrome, with the aim of evaluating their potential utility in diagnosing primary podocytopathies and predicting therapeutic response. Methods The study included a total of 72 patients diagnosed with nephrotic syndrome, alongside 21 healthy subjects for comparison. Among the patients, 38 were diagnosed with FSGS, 12 with MCD, and 22 with MN. The levels of anti-synaptopodin and anti-annexin-1 antibodies were quantified using Enzyme-Linked Immunosorbent Assay. Results The levels of antibodies to annexin 1 and anti-synaptopodin in the blood were found to be higher in patients diagnosed with MCD and FSGS compared to those with MN and healthy individuals. The elevated levels of antibodies to annexin 1 and synaptopodin showed area under the curve values of 0.826 (95% CI 0.732-0.923) and 0.827 (95% CI 0.741-0.879), respectively. However, a model incorporating both antibodies demonstrated higher sensitivity (80.9%) and specificity (81.3%) with an AUC of 0.859 (95% CI 0.760-0.957). Notably, serum levels of annexin 1 and anti-synaptopodin antibodies did not predict the response to prednisolone and/or CNI therapy. Discussion Levels of antibodies targeting synaptopodin and annexin 1 were notably elevated in patients diagnosed with MCD and FSGS compared to those with MN and healthy controls. A panel comprising both antibodies demonstrated moderate to high sensitivity and specificity for diagnosis MCD or FSGS.
Collapse
Affiliation(s)
- Natalia V. Chebotareva
- Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
| | | | - Evgenia A. Biryukova
- Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
| | | | - Igor I. Alentov
- Department of Prediction of Conservative Treatment Efficiency, Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Natalia S. Sergeeva
- Department of Prediction of Conservative Treatment Efficiency, Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Alexey S. Kononikhin
- Project Center of Advanced Mass, Spectrometry Technologies, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Evgeny N. Nikolaev
- Project Center of Advanced Mass, Spectrometry Technologies, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Sergey V. Moiseev
- Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
| |
Collapse
|
|
13
|
Meliambro K, He JC, Campbell KN. Podocyte-targeted therapies - progress and future directions. Nat Rev Nephrol 2024; 20:643-658. [PMID: 38724717 DOI: 10.1038/s41581-024-00843-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2024] [Indexed: 09/14/2024]
Abstract
Podocytes are the key target cells for injury across the spectrum of primary and secondary proteinuric kidney disorders, which account for up to 90% of cases of kidney failure worldwide. Seminal experimental and clinical studies have established a causative link between podocyte depletion and the magnitude of proteinuria in progressive glomerular disease. However, no substantial advances have been made in glomerular disease therapies, and the standard of care for podocytopathies relies on repurposed immunosuppressive drugs. The past two decades have seen a remarkable expansion in understanding of the mechanistic basis of podocyte injury, with prospects increasing for precision-based treatment approaches. Dozens of disease-causing genes with roles in the pathogenesis of clinical podocytopathies have been identified, as well as a number of putative glomerular permeability factors. These achievements, together with the identification of novel targets of podocyte injury, the development of potential approaches to harness the endogenous podocyte regenerative potential of progenitor cell populations, ongoing clinical trials of podocyte-specific pharmacological agents and the development of podocyte-directed drug delivery systems, contribute to an optimistic outlook for the future of glomerular disease therapy.
Collapse
Affiliation(s)
- Kristin Meliambro
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John C He
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kirk N Campbell
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| |
Collapse
|
|
14
|
Šakić Z, Atić A, Potočki S, Bašić-Jukić N. Sphingolipids and Chronic Kidney Disease. J Clin Med 2024; 13:5050. [PMID: 39274263 PMCID: PMC11396415 DOI: 10.3390/jcm13175050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/16/2024] Open
Abstract
Sphingolipids (SLs) are bioactive signaling molecules essential for various cellular processes, including cell survival, proliferation, migration, and apoptosis. Key SLs such as ceramides, sphingosine, and their phosphorylated forms play critical roles in cellular integrity. Dysregulation of SL levels is implicated in numerous diseases, notably chronic kidney disease (CKD). This review focuses on the role of SLs in CKD, highlighting their potential as biomarkers for early detection and prognosis. SLs maintain renal function by modulating the glomerular filtration barrier, primarily through the activity of podocytes. An imbalance in SLs can lead to podocyte damage, contributing to CKD progression. SL metabolism involves complex enzyme-catalyzed pathways, with ceramide serving as a central molecule in de novo and salvage pathways. Ceramides induce apoptosis and are implicated in oxidative stress and inflammation, while sphingosine-1-phosphate (S1P) promotes cell survival and vascular health. Studies have shown that SL metabolism disorders are linked to CKD progression, diabetic kidney disease, and glomerular diseases. Targeting SL pathways could offer novel therapeutic approaches for CKD. This review synthesizes recent research on SL signaling regulation in kidney diseases, emphasizing the importance of maintaining SL balance for renal health and the potential therapeutic benefits of modulating SL pathways.
Collapse
Affiliation(s)
- Zrinka Šakić
- Vuk Vrhovac University Clinic, Dugi dol 4a, 10000 Zagreb, Croatia
| | - Armin Atić
- Division of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, 10000 Zagreb, Croatia
| | - Slavica Potočki
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Nikolina Bašić-Jukić
- Division of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| |
Collapse
|
|
15
|
Le Berre L, Tilly G, Pilet P, Brouard S, Dantal J. The Immunosuppressive Drug LF15-0195 Acts Also on Glomerular Lesions, by a Change in Cytoskeleton Distribution in Podocyte. Am J Nephrol 2024; 55:583-596. [PMID: 39074452 DOI: 10.1159/000539965] [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: 03/08/2024] [Accepted: 06/18/2024] [Indexed: 07/31/2024]
Abstract
INTRODUCTION Buffalo/Mna rats spontaneously develop nephrotic syndrome (NS) which recurs after renal transplantation. The immunosuppressive drug LF15-0195 can promote regression of the initial and post-transplantation nephropathy via induction of regulatory T cells. We investigate if this drug has an additional effect on the expression and localization of podocyte specific proteins. METHODS Buffalo/Mna kidney samples were collected before and after the occurrence of proteinuria, and after the remission of proteinuria induced by LF15-0195 treatment and compared by quantitative RT-PCR, Western blot, electron, and confocal microscopy to kidney samples of age-matched healthy rats. Cytoskeleton changes were assessed in culture by stress fibers induction by TNFα. RESULTS We observed, by electron microscopy, a restoration of foot process architecture in the LF15-0195-treated Buff/Mna kidneys, consistent with proteinuria remission. Nephrin, podocin, CD2AP, and α-actinin-4 mRNA levels remained low during the active disease in the Buff/Mna, in comparison with healthy rats which increase, while podocalyxin and synaptopodin transcripts were elevated before the occurrence of the disease but did not differ from healthy animals after. No difference in the mRNA and protein expression between the untreated and the LF15-0195-treated proteinuric Buff/Mna were seen for these 6 proteins. No changes were observed by confocal microscopy in the protein distribution at a cellular level, but a more homogenous distribution similar to healthy rats, was observed within the glomeruli of LF15-0195-treated rats. In addition, LF15-0195 could partially restore actin cytoskeleton of endothelial cells in TNFα-induced-cell stress experiment. CONCLUSION The effect of LF15-0195 treatment appears to be mediated by 2 mechanisms: an immunomodulatory effect via regulatory T cells induction, described in our previous work and which can act on immune cell involved in the disease pathogenesis, and an effect on the restoration of podocyte cytoskeleton, independent of expression levels of the proteins involved in the slit diaphragm and podocyte function, showed in this article.
Collapse
Affiliation(s)
- Ludmilla Le Berre
- Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, CHU Nantes, Nantes Université, INSERM, Nantes, France
| | - Gaëlle Tilly
- Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, CHU Nantes, Nantes Université, INSERM, Nantes, France
| | - Paul Pilet
- Regenerative Medicine and Skeleton, RMeS, UMR 1229, Oniris, Nantes Université, INSERM, Nantes, France
| | - Sophie Brouard
- Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, CHU Nantes, Nantes Université, INSERM, Nantes, France
| | - Jacques Dantal
- Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, CHU Nantes, Nantes Université, INSERM, Nantes, France
| |
Collapse
|
|
16
|
Lee AM, Xu Y, Hu J, Xiao R, Hooper SR, Hartung EA, Coresh J, Rhee EP, Vasan RS, Kimmel PL, Warady BA, Furth SL, Denburg MR. Longitudinal Plasma Metabolome Patterns and Relation to Kidney Function and Proteinuria in Pediatric CKD. Clin J Am Soc Nephrol 2024; 19:837-850. [PMID: 38709558 PMCID: PMC11254025 DOI: 10.2215/cjn.0000000000000463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 04/29/2024] [Indexed: 05/08/2024]
Abstract
Key Points Longitudinal untargeted metabolomics. Children with CKD have a circulating metabolome that changes over time. Background Understanding plasma metabolome patterns in relation to changing kidney function in pediatric CKD is important for continued research for identifying novel biomarkers, characterizing biochemical pathophysiology, and developing targeted interventions. There are a limited number of studies of longitudinal metabolomics and virtually none in pediatric CKD. Methods The CKD in Children study is a multi-institutional, prospective cohort that enrolled children aged 6 months to 16 years with eGFR 30–90 ml/min per 1.73 m2. Untargeted metabolomics profiling was performed on plasma samples from the baseline, 2-, and 4-year study visits. There were technologic updates in the metabolomic profiling platform used between the baseline and follow-up assays. Statistical approaches were adopted to avoid direct comparison of baseline and follow-up measurements. To identify metabolite associations with eGFR or urine protein-creatinine ratio (UPCR) among all three time points, we applied linear mixed-effects (LME) models. To identify metabolites associated with time, we applied LME models to the 2- and 4-year follow-up data. We applied linear regression analysis to examine associations between change in metabolite level over time (∆level) and change in eGFR (∆eGFR) and UPCR (∆UPCR). We reported significance on the basis of both the false discovery rate (FDR) <0.05 and P < 0.05. Results There were 1156 person-visits (N : baseline=626, 2-year=254, 4-year=276) included. There were 622 metabolites with standardized measurements at all three time points. In LME modeling, 406 and 343 metabolites associated with eGFR and UPCR at FDR <0.05, respectively. Among 530 follow-up person-visits, 158 metabolites showed differences over time at FDR <0.05. For participants with complete data at both follow-up visits (n =123), we report 35 metabolites with ∆level–∆eGFR associations significant at FDR <0.05. There were no metabolites with significant ∆level–∆UPCR associations at FDR <0.05. We report 16 metabolites with ∆level–∆UPCR associations at P < 0.05 and associations with UPCR in LME modeling at FDR <0.05. Conclusions We characterized longitudinal plasma metabolomic patterns associated with eGFR and UPCR in a large pediatric CKD population. Many of these metabolite signals have been associated with CKD progression, etiology, and proteinuria in previous CKD Biomarkers Consortium studies. There were also novel metabolite associations with eGFR and proteinuria detected.
Collapse
Affiliation(s)
- Arthur M. Lee
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Yunwen Xu
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
| | - Jian Hu
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia
| | - Rui Xiao
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Stephen R. Hooper
- Department of Health Sciences, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
| | - Erum A. Hartung
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
- Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- NYU Grossman School of Medicine, New York, New York
| | - Eugene P. Rhee
- Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | - Ramachandran S. Vasan
- Boston University School of Medicine, Boston, Massachusetts
- Boston University School of Public Health, Boston, Massachusetts
| | - Paul L. Kimmel
- Division of Kidney, Urologic, and Hematologic Diseases, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
| | - Bradley A. Warady
- Division of Nephrology, Children’s Mercy Kansas City, Kansas City, Missouri
- University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Susan L. Furth
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania
- Department of Pediatrics and Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michelle R. Denburg
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Department of Pediatrics and Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| |
Collapse
|
|
17
|
Chen Y, Gong Y, Zou J, Li G, Zhang F, Yang Y, Liang Y, Dai W, He L, Lu H. Single-cell transcriptomic analysis reveals transcript enrichment in oxidative phosphorylation, fluid sheer stress, and inflammatory pathways in obesity-related glomerulopathy. Genes Dis 2024; 11:101101. [PMID: 38560497 PMCID: PMC10978546 DOI: 10.1016/j.gendis.2023.101101] [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: 11/16/2022] [Revised: 06/20/2023] [Accepted: 07/24/2023] [Indexed: 04/04/2024] Open
Abstract
Obesity-related glomerulopathy (ORG) is an independent risk factor for chronic kidney disease and even progression to end-stage renal disease. Efforts have been undertaken to elucidate the mechanisms underlying the development of ORG and substantial advances have been made in the treatment of ORG, but relatively little is known about cell-specific changes in gene expression. To define the transcriptomic landscape at single-cell resolution, we analyzed kidney samples from four patients with ORG and three obese control subjects without kidney disease using single-cell RNA sequencing. We report for the first time that immune cells, including T cells and B cells, are decreased in ORG patients. Further analysis indicated that SPP1 was significantly up-regulated in T cells and B cells. This gene is related to inflammation and cell proliferation. Analysis of differential gene expression in glomerular cells (endothelial cells, mesangial cells, and podocytes) showed that these cell types were mainly enriched in genes related to oxidative phosphorylation, cell adhesion, thermogenesis, and inflammatory pathways (PI3K-Akt signaling, MAPK signaling). Furthermore, we found that the podocytes of ORG patients were enriched in genes related to the fluid shear stress pathway. Moreover, an evaluation of cell-cell communications revealed that there were interactions between glomerular parietal epithelial cells and other cells in ORG patients, with major interactions between parietal epithelial cells and podocytes. Altogether, our identification of molecular events, cell types, and differentially expressed genes may facilitate the development of new preventive or therapeutic approaches for ORG.
Collapse
Affiliation(s)
- Yinyin Chen
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Yushun Gong
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Jia Zou
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Guoli Li
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Fan Zhang
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Yiya Yang
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Yumei Liang
- Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, Hunan 410000, China
| | - Wenni Dai
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410011, China
| | - Liyu He
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410011, China
| | - Hengcheng Lu
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan 410011, China
- Cardiovascular Research Institute of Jiangxi Province, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi 330006, China
| |
Collapse
|
|
18
|
Wang C, Zhang MZ, Li LX, Yun XY, Chen CM, Wang FF, Li B. Ultra-low-dose rituximab is effective for the treatment of patients with minimal change disease - A retrospective study. J Formos Med Assoc 2024:S0929-6646(24)00289-4. [PMID: 38906733 DOI: 10.1016/j.jfma.2024.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 06/04/2024] [Accepted: 06/14/2024] [Indexed: 06/23/2024] Open
Abstract
BACKGROUND PURPOSE Rituximab (RTX),an anti-CD20 monoclonal antibody can effectively treat minimal change disease (MCD),with low toxicity and a reduced steroid dosage. The optimal dosage of RTX for treating MCD remains unclear. This study aimed to investigate the efficacy of an ultra-low-dose regimen of RTX (100 mg per week for 4 weeks) for treating MCD. METHODS We retrospectively analyzed clinical data from 31 patients with MCD who received RTX. Seventeen patients received ultra-low-dose RTX (ULD-RTX) therapy, and 14 patients received standard-dose RTX (SD-RTX) therapy (500 mg weekly for 4 weeks). All patients were followed up for at least 6 months. RESULTS Both groups showed significant increases in the serum albumin levels and notable decreases in the urinary protein levels in the 1st and 6th months after RTX therapy. There were no significant differences in the plasma albumin or urinary protein levels between the groups (p > 0.05). B-cell depletion was observed in all patients after 1 month of RTX administration. At 6 months after RTX treatment, the remission rate was 93% in the SD-RTX group and 88% in the ULD-RTX group (p > 0.05). The ULD-RTX therapy incurred lower costs than did the SD-RTX therapy. One patient in the SD-RTX group developed community-acquired pneumonia. CONCLUSION Ultra-low-dose RTX is effective at inducing remission in patients with MCD at a lower cost.
Collapse
Affiliation(s)
- Chang Wang
- Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, China; Hainan Clinical Research Center for Urinary System Disease, China; National Health Commission Key Laboratory of Tropical Diseases Prevention and Control, China; Department of Nephrology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Man-Zhu Zhang
- Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, China; Hainan Clinical Research Center for Urinary System Disease, China; National Health Commission Key Laboratory of Tropical Diseases Prevention and Control, China
| | - Ling-Xu Li
- Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, China; Hainan Clinical Research Center for Urinary System Disease, China; National Health Commission Key Laboratory of Tropical Diseases Prevention and Control, China
| | - Xiao-Ying Yun
- Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, China; Hainan Clinical Research Center for Urinary System Disease, China; National Health Commission Key Laboratory of Tropical Diseases Prevention and Control, China
| | - Chun-Miao Chen
- Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, China; Hainan Clinical Research Center for Urinary System Disease, China; National Health Commission Key Laboratory of Tropical Diseases Prevention and Control, China
| | - Fei-Fei Wang
- Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, China; Hainan Clinical Research Center for Urinary System Disease, China; National Health Commission Key Laboratory of Tropical Diseases Prevention and Control, China
| | - Bing Li
- Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, China; Hainan Clinical Research Center for Urinary System Disease, China; National Health Commission Key Laboratory of Tropical Diseases Prevention and Control, China; Department of Nephrology, 2nd Affiliated Hospital of Harbin Medical University, Harbin, China.
| |
Collapse
|
|
19
|
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
|
|
20
|
Tolerico M, Merscher S, Fornoni A. Normal and Dysregulated Sphingolipid Metabolism: Contributions to Podocyte Injury and Beyond. Cells 2024; 13:890. [PMID: 38891023 PMCID: PMC11171506 DOI: 10.3390/cells13110890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/09/2024] [Accepted: 05/16/2024] [Indexed: 06/20/2024] Open
Abstract
Podocyte health is vital for maintaining proper glomerular filtration in the kidney. Interdigitating foot processes from podocytes form slit diaphragms which regulate the filtration of molecules through size and charge selectivity. The abundance of lipid rafts, which are ordered membrane domains rich in cholesterol and sphingolipids, near the slit diaphragm highlights the importance of lipid metabolism in podocyte health. Emerging research shows the importance of sphingolipid metabolism to podocyte health through structural and signaling roles. Dysregulation in sphingolipid metabolism has been shown to cause podocyte injury and drive glomerular disease progression. In this review, we discuss the structure and metabolism of sphingolipids, as well as their role in proper podocyte function and how alterations in sphingolipid metabolism contributes to podocyte injury and drives glomerular disease progression.
Collapse
Affiliation(s)
| | - Sandra Merscher
- Peggy and Harold Katz Family Drug Discovery Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| | - Alessia Fornoni
- Peggy and Harold Katz Family Drug Discovery Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA;
| |
Collapse
|
|
21
|
Song B, Jiang Y, Lin Y, Liu J, Jiang Y. Contribution of sphingomyelin phosphodiesterase acid-like 3B to the proliferation, migration, and invasion of ovarian cancer cells. Transl Cancer Res 2024; 13:1954-1968. [PMID: 38737677 PMCID: PMC11082662 DOI: 10.21037/tcr-24-309] [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: 02/27/2024] [Accepted: 04/18/2024] [Indexed: 05/14/2024]
Abstract
Background Cancer has the highest mortality rate among gynecological cancers and poses a serious threat to women's lives. However, the treatment options for ovarian cancer are still limited, and exploring effective targeted biomarkers is particularly important for predicting and treating ovarian cancer. Therefore, it is necessary to explore the molecular mechanisms of the occurrence and development of ovarian cancer. Methods This investigation encompassed the analysis of gene expression profiles, measurement of transcription levels of potential target genes in peripheral blood samples from ovarian cancer patients and characterization of the ovarian cancer-related secretory protein sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B). Through bioinformatics analysis, potential target genes were identified, and their association with overall survival (OS) and progression-free survival (PFS) in ovarian cancer patients was assessed utilizing relevant databases. Subsequently, differences in target gene expression in ovarian cancer tissue samples were validated through protein blotting and quantitative real-time PCR (qRT-qPCR). Cell proliferation assays using the cell count kit-8 (CCK-8) method, as well as transwell chamber assay and pre coated matrix gel chamber assay were employed to elucidate the role of SMPDL3B in ovarian cancer cell migration and invasion. Results This study revealed a substantial upregulation of SMPDL3B in the serum of ovarian cancer patients, correlating with an unfavorable prognosis. High SMPDL3B expression was linked not only to increased proliferation of ovarian cancer cells, but also enhanced migration and invasion. Remarkably, the knockdown the human alkaline ceramidase 2 (ACER2) gene in cancer cells with heightened SMPDL3B expression significantly inhibited cell proliferation, migration, and invasion induced by SMPDL3B activation (P<0.05), highlighting the functional interplay between ACER2 and SMPDL3B in ovarian cancer. Conclusions In summary, this study proposes SMPDL3B as a prognostic marker for ovarian cancer, with implications for potential therapeutic intervention targeting the ACER2-SMPDL3B axis.
Collapse
Affiliation(s)
- Baozhi Song
- Department of Gynecology, Shengli Clinical Medical College of Fujian Medical University & Fujian Provincial Hospital, Fuzhou, China
| | - Yu Jiang
- Department of Gynecology, Shengli Clinical Medical College of Fujian Medical University & Fujian Provincial Hospital, Fuzhou, China
| | - Ying Lin
- Department of Pathology, Shengli Clinical Medical College of Fujian Medical University & Fujian Provincial Hospital, Fuzhou, China
| | - Jiahua Liu
- Department of Gynecology, Shengli Clinical Medical College of Fujian Medical University & Fujian Provincial Hospital, Fuzhou, China
| | - Yatao Jiang
- Department of Obstetrics, Shengli Clinical Medical College of Fujian Medical University & Fujian Provincial Hospital, Fuzhou, China
| |
Collapse
|
|
22
|
Mirioglu S, Daniel-Fischer L, Berke I, Ahmad SH, Bajema IM, Bruchfeld A, Fernandez-Juarez GM, Floege J, Frangou E, Goumenos D, Griffith M, Moran SM, van Kooten C, Steiger S, Stevens KI, Turkmen K, Willcocks LC, Kronbichler A. Management of adult patients with podocytopathies: an update from the ERA Immunonephrology Working Group. Nephrol Dial Transplant 2024; 39:569-580. [PMID: 38341276 PMCID: PMC11024823 DOI: 10.1093/ndt/gfae025] [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: 11/14/2023] [Indexed: 02/12/2024] Open
Abstract
The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are entities without immune complex deposits which can cause podocyte injury, thus are frequently grouped under the umbrella of podocytopathies. Whether MCD and FSGS may represent a spectrum of the same disease remains a matter of conjecture. Both frequently require repeated high-dose glucocorticoid therapy with alternative immunosuppressive treatments reserved for relapsing or resistant cases and response rates are variable. There is an unmet need to identify patients who should receive immunosuppressive therapies as opposed to those who would benefit from supportive strategies. Therapeutic trials focusing on MCD are scarce, and the evidence used for the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the management of glomerular diseases largely stems from observational and pediatric trials. In FSGS, the differentiation between primary forms and those with underlying genetic variants or secondary forms further complicates trial design. This article provides a perspective of the Immunonephrology Working Group (IWG) of the European Renal Association (ERA) and discusses the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases focusing on the management of MCD and primary forms of FSGS in the context of recently published evidence, with a special emphasis on the role of rituximab, cyclophosphamide, supportive treatment options and ongoing clinical trials in the field.
Collapse
Affiliation(s)
- Safak Mirioglu
- Division of Nephrology, Bezmialem Vakif University School of Medicine, Istanbul, Turkey
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Lisa Daniel-Fischer
- Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Ilay Berke
- Division of Nephrology, Marmara University School of Medicine, Istanbul, Turkey
| | - Syed Hasan Ahmad
- Department of Renal Medicine, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK
| | - Ingeborg M Bajema
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Annette Bruchfeld
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
- Department of Renal Medicine, Karolinska University Hospital and CLINTEC Karolinska Institutet, Stockholm, Sweden
| | | | - Jürgen Floege
- Division of Nephrology, RWTH Aachen University Hospital, Aachen, Germany
| | - Eleni Frangou
- Department of Nephrology, Limassol General Hospital, Limassol, Cyprus; University of Nicosia Medical School, Nicosia, Cyprus
| | - Dimitrios Goumenos
- Department of Nephrology and Renal Transplantation, Patras University Hospital, Patras, Greece
| | - Megan Griffith
- Imperial College Healthcare NHS Trust Renal and Transplant Centre, Hammersmith Hospital, London, United Kingdom
| | - Sarah M Moran
- Cork University Hospital, University College Cork, Cork, Ireland
| | - Cees van Kooten
- Division of Nephrology and Transplant Medicine, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Stefanie Steiger
- Division of Nephrology, Department of Internal Medicine IV, Hospital of the Ludwig-Maximilians-University, Munich, Germany
| | - Kate I Stevens
- Glasgow Renal and Transplant Unit, Queen Elizabeth University Hospital, Glasgow, UK
| | - Kultigin Turkmen
- Division of Nephrology, Department of Internal Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Lisa C Willcocks
- Department of Renal Medicine, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK
| | - Andreas Kronbichler
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria
| |
Collapse
|
|
23
|
Jiang H, Shen Z, Zhuang J, Lu C, Qu Y, Xu C, Yang S, Tian X. Understanding the podocyte immune responses in proteinuric kidney diseases: from pathogenesis to therapy. Front Immunol 2024; 14:1335936. [PMID: 38288116 PMCID: PMC10822972 DOI: 10.3389/fimmu.2023.1335936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 12/29/2023] [Indexed: 01/31/2024] Open
Abstract
The glomerular filtration barrier, comprising the inner layer of capillary fenestrated endothelial cells, outermost podocytes, and the glomerular basement membrane between them, plays a pivotal role in kidney function. Podocytes, terminally differentiated epithelial cells, are challenging to regenerate once injured. They are essential for maintaining the integrity of the glomerular filtration barrier. Damage to podocytes, resulting from intrinsic or extrinsic factors, leads to proteinuria in the early stages and eventually progresses to chronic kidney disease (CKD). Immune-mediated podocyte injury is a primary pathogenic mechanism in proteinuric glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and lupus nephritis with podocyte involvement. An extensive body of evidence indicates that podocytes not only contribute significantly to the maintenance of the glomerular filtration barrier and serve as targets of immune responses but also exhibit immune cell-like characteristics, participating in both innate and adaptive immunity. They play a pivotal role in mediating glomerular injury and represent potential therapeutic targets for CKD. This review aims to systematically elucidate the mechanisms of podocyte immune injury in various podocyte lesions and provide an overview of recent advances in podocyte immunotherapy. It offers valuable insights for a deeper understanding of the role of podocytes in proteinuric glomerular diseases, and the identification of new therapeutic targets, and has significant implications for the future clinical diagnosis and treatment of podocyte-related disorders.
Collapse
Affiliation(s)
- Hong Jiang
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Zhirang Shen
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Jing Zhuang
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Chen Lu
- Division of Nephrology, Department of Internal Medicine, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Yue Qu
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Chengren Xu
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Shufen Yang
- Division of Nephrology, Department of Internal Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Xuefei Tian
- Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
| |
Collapse
|
|
24
|
Ma S, Qiu Y, Zhang C. Cytoskeleton Rearrangement in Podocytopathies: An Update. Int J Mol Sci 2024; 25:647. [PMID: 38203817 PMCID: PMC10779434 DOI: 10.3390/ijms25010647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/14/2023] [Accepted: 01/01/2024] [Indexed: 01/12/2024] Open
Abstract
Podocyte injury can disrupt the glomerular filtration barrier (GFB), leading to podocytopathies that emphasize podocytes as the glomerulus's key organizer. The coordinated cytoskeleton is essential for supporting the elegant structure and complete functions of podocytes. Therefore, cytoskeleton rearrangement is closely related to the pathogenesis of podocytopathies. In podocytopathies, the rearrangement of the cytoskeleton refers to significant alterations in a string of slit diaphragm (SD) and focal adhesion proteins such as the signaling node nephrin, calcium influx via transient receptor potential channel 6 (TRPC6), and regulation of the Rho family, eventually leading to the disorganization of the original cytoskeletal architecture. Thus, it is imperative to focus on these proteins and signaling pathways to probe the cytoskeleton rearrangement in podocytopathies. In this review, we describe podocytopathies and the podocyte cytoskeleton, then discuss the molecular mechanisms involved in cytoskeleton rearrangement in podocytopathies and summarize the effects of currently existing drugs on regulating the podocyte cytoskeleton.
Collapse
Affiliation(s)
| | | | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (S.M.); (Y.Q.)
| |
Collapse
|
|
25
|
Zhan HQ, Zhang X, Chen XL, Cheng L, Wang X. Application of nanotechnology in the treatment of glomerulonephritis: current status and future perspectives. J Nanobiotechnology 2024; 22:9. [PMID: 38169389 PMCID: PMC10763010 DOI: 10.1186/s12951-023-02257-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 12/07/2023] [Indexed: 01/05/2024] Open
Abstract
Glomerulonephritis (GN) is the most common cause of end-stage renal failure worldwide; in most cases, it cannot be cured and can only delay the progression of the disease. At present, the main treatment methods include symptomatic therapy, immunosuppressive therapy, and renal replacement therapy. However, effective treatment of GN is hindered by issues such as steroid resistance, serious side effects, low bioavailability, and lack of precise targeting. With the widespread application of nanoparticles in medical treatment, novel methods have emerged for the treatment of kidney diseases. Targeted transportation of drugs, nucleic acids, and other substances to kidney tissues and even kidney cells through nanodrug delivery systems can reduce the systemic effects and adverse reactions of drugs and improve treatment effectiveness. The high specificity of nanoparticles enables them to bind to ion channels and block or enhance channel gating, thus improving inflammation. This review briefly introduces the characteristics of GN, describes the treatment status of GN, systematically summarizes the research achievements of nanoparticles in the treatment of primary GN, diabetic nephropathy and lupus nephritis, analyzes recent therapeutic developments, and outlines promising research directions, such as gas signaling molecule nanodrug delivery systems and ultrasmall nanoparticles. The current application of nanoparticles in GN is summarized to provide a reference for better treatment of GN in the future.
Collapse
Affiliation(s)
- He-Qin Zhan
- Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Department of Pathology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
| | - Xiaoxun Zhang
- Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Xu-Lin Chen
- Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People's Republic of China
| | - Liang Cheng
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, People's Republic of China
| | - Xianwen Wang
- School of Biomedical Engineering, Research and Engineering Center of Biomedical Materials, Anhui Medical University, Hefei, 230032, China.
| |
Collapse
|
|
26
|
Costa C, Antunes A, Oliveira J, Pereira M, Godinho I, Fernandes P, Jorge S, Lopes JA, Gameiro J. Rituximab in Steroid-Dependent Podocytopathies. GLOMERULAR DISEASES 2024; 4:129-136. [PMID: 39144474 PMCID: PMC11324230 DOI: 10.1159/000539922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 06/17/2024] [Indexed: 08/16/2024]
Abstract
Introduction Rituximab (RTX) has been reported as an effective treatment alternative in primary forms of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) associated with steroid dependence and frequent relapses. However, the optimal RTX regimen and the outcomes of further doses of RTX remain unclear. This study aimed to evaluate the use of induction and maintenance RTX therapy for adults with primary podocytopathies. Methods We performed a retrospective case series on adult patients with steroid-dependent podocytopathies who received an induction RTX therapy. Maintenance therapy was performed at physician's discretion. Remission and relapse rates, concomitant corticosteroids and immunosuppressants use, B-cell depletion and adverse events were analyzed. Results Fourteen patients (mean age at start of RTX 29.1 ± 21.9 years) with MCD (n = 7) or FSGS (n = 7) were treated with 2 doses of 1,000 mg 2 weeks apart (n = 13) or four doses of 375 mg/m2 (n = 1) of RTX. At last follow-up (mean 47.3 ± 101.7 months), 10 patients were in complete remission and two remained in partial remission. A reduction in the number of relapses, number of patients under corticosteroids and immunosuppressants, and dose of prednisolone was observed when compared to baseline (14 [100%] vs. 5 [35.7%]; 8/14 [57.1%] vs. 4/12 [33.3%]; 13/14 [92.9%] vs. 7/12 [58.3%]; 20 mg/day vs. 5.25 mg/day, respectively). Maintenance RTX therapy was used in 6 patients, with sustained complete remission. Infusion reactions were observed in 4 patients (one required treatment withdrawal). Conclusions Our findings support the use of RTX for a steroid-free remission in podocytopathies and suggest that maintenance RTX is well-tolerated and associated with prolonged remission. Further studies are needed to confirm its efficacy and safety and establish the optimal induction and maintenance RTX regimen in steroid-dependent podocytopathies.
Collapse
Affiliation(s)
- Cláudia Costa
- Serviço de Nefrologia e Transplantação Renal, Unidade Local de Saúde Santa Maria, Lisboa, Portugal
| | - Amélia Antunes
- Clínica Universitária de Nefrologia, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
| | - João Oliveira
- Serviço de Nefrologia e Transplantação Renal, Unidade Local de Saúde Santa Maria, Lisboa, Portugal
| | - Marta Pereira
- Serviço de Nefrologia e Transplantação Renal, Unidade Local de Saúde Santa Maria, Lisboa, Portugal
| | - Iolanda Godinho
- Serviço de Nefrologia e Transplantação Renal, Unidade Local de Saúde Santa Maria, Lisboa, Portugal
| | - Paulo Fernandes
- Serviço de Nefrologia e Transplantação Renal, Unidade Local de Saúde Santa Maria, Lisboa, Portugal
| | - Sofia Jorge
- Serviço de Nefrologia e Transplantação Renal, Unidade Local de Saúde Santa Maria, Lisboa, Portugal
| | - José António Lopes
- Serviço de Nefrologia e Transplantação Renal, Unidade Local de Saúde Santa Maria, Lisboa, Portugal
- Clínica Universitária de Nefrologia, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
| | - Joana Gameiro
- Serviço de Nefrologia e Transplantação Renal, Unidade Local de Saúde Santa Maria, Lisboa, Portugal
- Clínica Universitária de Nefrologia, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
| |
Collapse
|
|
27
|
Lee AM, Xu Y, Hooper SR, Abraham AG, Hu J, Xiao R, Matheson MB, Brunson C, Rhee EP, Coresh J, Vasan RS, Schrauben S, Kimmel PL, Warady BA, Furth SL, Hartung EA, Denburg MR. Circulating Metabolomic Associations with Neurocognitive Outcomes in Pediatric CKD. Clin J Am Soc Nephrol 2024; 19:13-25. [PMID: 37871960 PMCID: PMC10843217 DOI: 10.2215/cjn.0000000000000318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 10/16/2023] [Indexed: 10/25/2023]
Abstract
BACKGROUND Children with CKD are at risk for impaired neurocognitive functioning. We investigated metabolomic associations with neurocognition in children with CKD. METHODS We leveraged data from the Chronic Kidney Disease in Children (CKiD) study and the Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease (NiCK) study. CKiD is a multi-institutional cohort that enrolled children aged 6 months to 16 years with eGFR 30-90 ml/min per 1.73 m 2 ( n =569). NiCK is a single-center cross-sectional study of participants aged 8-25 years with eGFR<90 ml/min per 1.73 m 2 ( n =60) and matched healthy controls ( n =67). Untargeted metabolomic quantification was performed on plasma (CKiD, 622 metabolites) and serum (NiCK, 825 metabolites) samples. Four neurocognitive domains were assessed: intelligence, attention regulation, working memory, and parent ratings of executive function. Repeat assessments were performed in CKiD at 2-year intervals. Linear regression and linear mixed-effects regression analyses adjusting for age, sex, delivery history, hypertension, proteinuria, CKD duration, and glomerular versus nonglomerular diagnosis were used to identify metabolites associated with neurocognitive z-scores. Analyses were performed with and without adjustment for eGFR. RESULTS There were multiple metabolite associations with neurocognition observed in at least two of the analytic samples (CKiD baseline, CKiD follow-up, and NiCK CKD). Most of these metabolites were significantly elevated in children with CKD compared with healthy controls in NiCK. Notable signals included associations with parental ratings of executive function: phenylacetylglutamine, indoleacetylglutamine, and trimethylamine N-oxide-and with intelligence: γ -glutamyl amino acids and aconitate. CONCLUSIONS Several metabolites were associated with neurocognitive dysfunction in pediatric CKD, implicating gut microbiome-derived substances, mitochondrial dysfunction, and altered energy metabolism, circulating toxins, and redox homeostasis. PODCAST This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_11_17_CJN0000000000000318.mp3.
Collapse
Affiliation(s)
- Arthur M. Lee
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Yunwen Xu
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
| | - Stephen R. Hooper
- Department of Health Sciences, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
| | - Alison G. Abraham
- Department of Epidemiology, Colorado University School of Public Health, Aurora, Colorado
| | - Jian Hu
- Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia
| | - Rui Xiao
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Matthew B. Matheson
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
| | - Celina Brunson
- Division of Nephrology, Children's National Hospital, Washington, DC
| | - Eugene P. Rhee
- Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts
- Harvard School of Medicine, Boston, Massachusetts
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ramachandran S. Vasan
- Boston University School of Medicine, Boston, Massachusetts
- Boston University School of Public Health, Boston, Massachusetts
| | - Sarah Schrauben
- Perelman School of Medicine at the University of Pennsylvania, Department of Medicine and Department of Biostatistics, Epidemiology, and Informatics, Philadelphia, Pennsylvania
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Paul L. Kimmel
- Division of Kidney, Urologic, and Hematologic Diseases, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland
| | - Bradley A. Warady
- Division of Nephrology, Children's Mercy Kansas City, Kansas City, Missouri
- University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Susan L. Furth
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania
- Perelman School of Medicine at the University of Pennsylvania, Department of Pediatrics and Department of Biostatistics, Epidemiology, and Informatics, Philadelphia, Pennsylvania
| | - Erum A. Hartung
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Perelman School of Medicine at the University of Pennsylvania, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michelle R. Denburg
- Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Perelman School of Medicine at the University of Pennsylvania, Department of Pediatrics and Department of Biostatistics, Epidemiology, and Informatics, Philadelphia, Pennsylvania
| |
Collapse
|
|
28
|
Gipson DS, Wang CS, Salmon E, Gbadegesin R, Naik A, Sanna-Cherchi S, Fornoni A, Kretzler M, Merscher S, Hoover P, Kidwell K, Saleem M, Riella L, Holzman L, Jackson A, Olabisi O, Cravedi P, Freedman BS, Himmelfarb J, Vivarelli M, Harder J, Klein J, Burke G, Rheault M, Spino C, Desmond HE, Trachtman H. FSGS Recurrence Collaboration: Report of a Symposium. GLOMERULAR DISEASES 2024; 4:1-10. [PMID: 38348154 PMCID: PMC10859699 DOI: 10.1159/000535138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 10/30/2023] [Indexed: 02/15/2024]
Affiliation(s)
- Debbie S. Gipson
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
| | - Chia-Shi Wang
- Department of Pediatrics, Emory University, Atlanta, GA, USA
| | - Eloise Salmon
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
| | - Rasheed Gbadegesin
- Department of Medicine, Duke University, Durham, NC, USA
- Department of Pediatrics, Duke University, Durham, NC, USA
| | - Abhijit Naik
- Department of Medicine, University of Michigan, Ann Arbor, MI, USA
| | | | | | - Matthias Kretzler
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | | | - Paul Hoover
- Department of Medicine, Harvard University, Cambridge, MA, USA
| | - Kelley Kidwell
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Moin Saleem
- Translational Health Sciences, University of Bristol, Bristol, UK
| | - Leonardo Riella
- Department of Medicine, Harvard University, Cambridge, MA, USA
| | - Lawrence Holzman
- Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | | | | | - Paolo Cravedi
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | - Marina Vivarelli
- Department of Pediatric Subspecialties, Bambino Gesù Children’s Hospital, Rome, Italy
| | - Jennifer Harder
- Department of Internal Medicine, University of Louisville, Louisville, KY, USA
| | - Jon Klein
- Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - George Burke
- Department of Surgery, University of Miami, Miami, FL, USA
| | - Michelle Rheault
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
| | - Cathie Spino
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Hailey E. Desmond
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
| | - Howard Trachtman
- Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA
| |
Collapse
|
|
29
|
Kaya M, Girişgen İ, Yalçın N, Becerir T, Şenol H, Gülten G, Yüksel S. The Importance of Sphingomyelin Phosphodiesterase Acid-Like 3b (SMPDL-3b) Levels in Kidney Biopsy Specimens of Children With Nephrotic Syndrome. Fetal Pediatr Pathol 2023; 42:936-949. [PMID: 37818552 DOI: 10.1080/15513815.2023.2267683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 09/29/2023] [Indexed: 10/12/2023]
Abstract
OBJECTIVE It remains unclear whether the low amount of SMPDL-3b required for rituximab binding is the cause of treatment resistance in patients with treatment-resistant nephrotic syndrome with advanced podocyte injury. Given the limited number of studies on the relationship between rituximab and SMPDL-3b, this study was conducted to assess whether SMPDL-3b levels in pretreatment renal biopsy specimens can be used to predict the clinical effectiveness of immunosuppressive drugs, especially rituximab, in children with nephrotic syndrome. METHODS Kidney biopsy specimens from 44 patients diagnosed with idiopatic nephrotic syndrome were analyzed using immunohistochemical staining with an anti-SMPDL-3b antibody and real-time polymerase chain reaction (PCR) for SMPDL-3b mRNA expression. RESULTS We showed that SMPDL-3b mRNA expression and anti-SMPDL-3b antibody staining did not differ significantly between the patient groups with different responses to immunosuppressive therapies. CONCLUSION Our results suggest that SMPDL-3b may actually be an indicator of disease progression rather than a marker for predicting response to a particular immunosuppressive agent.
Collapse
Affiliation(s)
- Muhammet Kaya
- Department of Pediatric Nephrology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - İlknur Girişgen
- Department of Pediatric Nephrology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Nagihan Yalçın
- Department of Pathology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Tülay Becerir
- Department of Pediatric Nephrology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Hande Şenol
- Department of Biostatistics, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Gülsün Gülten
- Department of Pathology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| | - Selcuk Yüksel
- Department of Pediatric Nephrology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
| |
Collapse
|
|
30
|
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
|
|
31
|
Veissi ST, van den Berge T, van Wijk JAE, van der Velden T, Classens R, Lunsonga L, Brockotter R, Kaffa C, Bervoets S, Smeets B, van den Heuvel LPWJ, Schreuder MF. Levamisole Modulation of Podocytes' Actin Cytoskeleton in Nephrotic Syndrome. Biomedicines 2023; 11:3039. [PMID: 38002039 PMCID: PMC10669662 DOI: 10.3390/biomedicines11113039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 10/31/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023] Open
Abstract
Podocytes play a central role in glomerular diseases such as (idiopathic) nephrotic syndrome (iNS). Glucocorticoids are the gold standard therapy for iNS. Nevertheless, frequent relapses are common. In children with iNS, steroid-sparing agents are used to avoid prolonged steroid use and reduce steroid toxicity. Levamisole is one of these steroid-sparing drugs and although clinical effectiveness has been demonstrated, the molecular mechanisms of how levamisole exerts its beneficial effects remains poorly studied. Apart from immunomodulatory capacities, nonimmunological effects of levamisole on podocytes have also been suggested. We aimed to elaborate on the effects of levamisole on human podocytes in iNS. RNA sequencing data from a human podocyte cell line treated with levamisole showed that levamisole modulates the expression of various genes involved in actin cytoskeleton stabilization and remodeling. Functional experiments showed that podocytes exposed to puromycin aminonucleoside (PAN), lipopolysaccharides (LPS), and NS patient plasma resulted in significant actin cytoskeleton derangement, reduced cell motility, and impaired cellular adhesion when compared to controls, effects that could be restored by levamisole. Mechanistic studies revealed that levamisole exerts its beneficial effects on podocytes by signaling through the glucocorticoid receptor and by regulating the activity of Rho GTPases. In summary, our data show that levamisole exerts beneficial effects on podocytes by stabilizing the actin cytoskeleton in a glucocorticoid receptor-dependent manner.
Collapse
Affiliation(s)
- Susan T Veissi
- Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Tijmen van den Berge
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Joanna A E van Wijk
- Department of Pediatric Nephrology, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Thea van der Velden
- Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - René Classens
- Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Lynn Lunsonga
- Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Rick Brockotter
- Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Charlotte Kaffa
- Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Sander Bervoets
- Center for Molecular and Biomolecular Informatics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Bart Smeets
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Lambertus P W J van den Heuvel
- Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Department of Development and Regeneration, University Hospital Leuven, 3000 Leuven, Belgium
| | - Michiel F Schreuder
- Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| |
Collapse
|
|
32
|
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
|
|
33
|
Angeletti A, Bruschi M, Kajana X, La Porta E, Spinelli S, Caridi G, Lugani F, Verrina EE, Ghiggeri GM. Biologics in steroid resistant nephrotic syndrome in childhood: review and new hypothesis-driven treatment. Front Immunol 2023; 14:1213203. [PMID: 37705972 PMCID: PMC10497215 DOI: 10.3389/fimmu.2023.1213203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/14/2023] [Indexed: 09/15/2023] Open
Abstract
Nephrotic syndrome affects about 2-7 per 100,000 children yearly and accounts for less than 15% of end stage kidney disease. Steroids still represent the cornerstone of therapy achieving remission in 75-90% of the cases The remaining part result as steroid resistant nephrotic syndrome, characterized by the elevated risk of developing end stage kidney disease and frequently presenting disease recurrence in case of kidney transplant. The pathogenesis of nephrotic syndrome is still far to be elucidated, however, efficacy of immune treatments provided the basis to suggest the involvement of the immune system in the pathogenesis of the disease. Based on these substrates, more immune drugs, further than steroids, were administered in steroid resistant nephrotic syndrome, such as antiproliferative and alkylating agents or calcineurin inhibitors. However, such treatments failed in inducing a sustained remission. In last two decades, the developments of monoclonal antibodies, including the anti-CD20 rituximab and inhibitor of B7-1 abatacept, represented a valid opportunity of treatment. However, also the effectiveness of biologics resulted limited. We here propose a new hypothesis-driven treatment based on the combining administration of rituximab with the anti-CD38 monoclonal antibody daratumumab (NCT05704400), sustained by the hypothesis to target the entire B-cells subtypes pool, including the long-lived plasmacells.
Collapse
Affiliation(s)
- Andrea Angeletti
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Maurizio Bruschi
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Xhuliana Kajana
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Edoardo La Porta
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Sonia Spinelli
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Gianluca Caridi
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Francesca Lugani
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Enrico Eugenio Verrina
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Gian Marco Ghiggeri
- Division of Nephrology, Dialysis, Transplantation, IRCCS Istituto Giannina Gaslini, Genova, Italy
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| |
Collapse
|
|
34
|
Hackl A, Nüsken E, Voggel J, Abo Zed SED, Binz-Lotter J, Unnersjö-Jess D, Müller C, Fink G, Bohl K, Wiesner E, Diefenhardt P, Dafinger C, Chen H, Wohlfarth M, Müller RU, Hackl MJ, Schermer B, Nüsken KD, Weber LT. The effect of mycophenolate mofetil on podocytes in nephrotoxic serum nephritis. Sci Rep 2023; 13:14167. [PMID: 37644089 PMCID: PMC10465485 DOI: 10.1038/s41598-023-41222-1] [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: 04/28/2023] [Accepted: 08/23/2023] [Indexed: 08/31/2023] Open
Abstract
Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca2+-actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) for one week. On day 10, we performed proteomic analysis of glomeruli as well as super-resolution imaging of the slit diaphragm. For multiphoton imaging of Ca2+ concentration ([Ca2+]i), the experimental design was repeated in mice expressing podocyte-specific Ca2+ sensor. MMF ameliorated the proteinuria and crescent formation induced by NTS. We identified significant changes in the abundance of proteins involved in Ca2+ signaling and actin cytoskeleton regulation, which was further confirmed by direct [Ca2+]i imaging in podocytes showing decreased Ca2+ levels after MMF treatment. This was associated with a tendency to restoration of podocyte foot process structure. Here, we provide evidence that MPA has a substantial direct effect on podocytes. MMF contributes to improvement of [Ca2+]i and amelioration of the disorganized actin cytoskeleton in podocytes. These data extend the knowledge of direct effects of immunosuppressants on podocytes that may contribute to a more effective treatment of proteinuric glomerulopathies with the least possible side effects.
Collapse
Affiliation(s)
- A Hackl
- Department of Pediatrics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Kerpener Street 62, 50937, Cologne, Germany.
- CECAD, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
| | - E Nüsken
- Department of Pediatrics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Kerpener Street 62, 50937, Cologne, Germany
| | - J Voggel
- Department of Pediatrics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Kerpener Street 62, 50937, Cologne, Germany
| | - S E D Abo Zed
- Department of Pediatrics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Kerpener Street 62, 50937, Cologne, Germany
- CECAD, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - J Binz-Lotter
- CECAD, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department 2 of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - D Unnersjö-Jess
- CECAD, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department 2 of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - C Müller
- Department of Therapeutic Drug Monitoring, Pharmacology at the Laboratory Centre, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - G Fink
- Department of Pediatrics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Kerpener Street 62, 50937, Cologne, Germany
| | - K Bohl
- CECAD, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department 2 of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - E Wiesner
- CECAD, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department 2 of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - P Diefenhardt
- CECAD, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department 2 of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - C Dafinger
- Department of Pediatrics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Kerpener Street 62, 50937, Cologne, Germany
- CECAD, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - H Chen
- CECAD, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department 2 of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - M Wohlfarth
- Department of Pediatrics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Kerpener Street 62, 50937, Cologne, Germany
| | - R-U Müller
- CECAD, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department 2 of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Rare Kidney Diseases Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - M J Hackl
- CECAD, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department 2 of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - B Schermer
- CECAD, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
- Department 2 of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| | - K-D Nüsken
- Department of Pediatrics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Kerpener Street 62, 50937, Cologne, Germany
| | - L T Weber
- Department of Pediatrics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Kerpener Street 62, 50937, Cologne, Germany
- Center for Rare Kidney Diseases Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany
| |
Collapse
|
|
35
|
Morris AD, Floyd L, Woywodt A, Dhaygude A. Rituximab in the treatment of primary FSGS: time for its use in routine clinical practice? Clin Kidney J 2023; 16:1199-1205. [PMID: 37529639 PMCID: PMC10387384 DOI: 10.1093/ckj/sfad122] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Indexed: 08/03/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome and whilst advances have been made in the pathophysiology, diagnostics and management of other podocytopathies, primary FSGS remains the most elusive. It has been assumed for a long time that a circulatory permeability factor exists that mediates podocyte injury, and the potential for autoantibody-mediated disease therefore raises the question as to whether patients may benefit from targeted B-cell therapy with rituximab. The prospective case series of seven patients by Roccatello et al. adds to the limited but growing evidence suggesting that B-cell depletion therapy can be safe and effective in the treatment of primary FSGS. In this editorial we explore the available evidence that suggests how and in whom rituximab may play a role in the management of primary FSGS, as well as the limitations and other potential future treatments. Further research and randomized controlled trials are needed to include larger numbers of patients, feature genetic screening and incorporate data on B-cell kinetics as a potential guide for dosing and frequency of rituximab.
Collapse
Affiliation(s)
| | - Lauren Floyd
- Department of Nephrology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
| | - Alexander Woywodt
- Department of Nephrology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
| | - Ajay Dhaygude
- Department of Nephrology, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, UK
| |
Collapse
|
|
36
|
Burke GW, Mitrofanova A, Fontanella A, Ciancio G, Roth D, Ruiz P, Abitbol C, Chandar J, Merscher S, Fornoni A. The podocyte: glomerular sentinel at the crossroads of innate and adaptive immunity. Front Immunol 2023; 14:1201619. [PMID: 37564655 PMCID: PMC10410139 DOI: 10.3389/fimmu.2023.1201619] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 06/26/2023] [Indexed: 08/12/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a common glomerular disorder that manifests clinically with the nephrotic syndrome and has a propensity to recur following kidney transplantation. The pathophysiology and therapies available to treat FSGS currently remain elusive. Since the podocyte appears to be the target of apparent circulating factor(s) that lead to recurrence of proteinuria following kidney transplantation, this article is focused on the podocyte. In the context of kidney transplantation, the performance of pre- and post-reperfusion biopsies, and the establishment of in vitro podocyte liquid biopsies/assays allow for the development of clinically relevant studies of podocyte biology. This has given insight into new pathways, involving novel targets in innate and adaptive immunity, such as SMPDL3b, cGAS-STING, and B7-1. Elegant experimental studies suggest that the successful clinical use of rituximab and abatacept, two immunomodulating agents, in our case series, may be due to direct effects on the podocyte, in addition to, or perhaps distinct from their immunosuppressive functions. Thus, tissue biomarker-directed therapy may provide a rational approach to validate the mechanism of disease and allow for the development of new therapeutics for FSGS. This report highlights recent progress in the field and emphasizes the importance of kidney transplantation and recurrent FSGS (rFSGS) as a platform for the study of primary FSGS.
Collapse
Affiliation(s)
- George W. Burke
- Division of Kidney−Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Alla Mitrofanova
- Research, Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Antonio Fontanella
- Research, Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Gaetano Ciancio
- Division of Kidney−Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - David Roth
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, and the Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Phil Ruiz
- Transplant Pathology, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Carolyn Abitbol
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Jayanthi Chandar
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Sandra Merscher
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
| |
Collapse
|
|
37
|
Rheault MN, Amaral S, Bock M, Chambers ET, Chavers B, Ters ME, Garro R, Gbadegesin R, Govil A, Harshman L, Amer H, Hooper DK, Israni AK, Riad S, Sageshima J, Shapiro R, Seifert M, Smith J, Sung R, Thomas CP, Wang Q, Verghese PS. A randomized controlled trial of preemptive rituximab to prevent recurrent focal segmental glomerulosclerosis post-kidney transplant (PRI-VENT FSGS): protocol and study design. FRONTIERS IN NEPHROLOGY 2023; 3:1181076. [PMID: 37675355 PMCID: PMC10479749 DOI: 10.3389/fneph.2023.1181076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 04/17/2023] [Indexed: 09/08/2023]
Abstract
Background Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease requiring kidney transplantation and can recur in the allograft in 30-80% of recipients resulting in reduced graft survival. Plasmapheresis has shown efficacy in treating some cases of recurrent FSGS but isolated plasmapheresis has not demonstrated efficacy in preventing recurrent FSGS. Rituximab has had anecdotal success in preventing recurrence in a single center study but has not been studied in combination with plasmapheresis for preventing FSGS recurrence. Methods We are conducting a randomized, controlled, multicenter clinical trial of adult and pediatric kidney transplant recipients with primary FSGS to assess whether plasmapheresis in combination with rituximab prevents recurrent disease post-transplantation. Discussion Rituximab combined with plasmapheresis is a promising, novel therapy to prevent recurrent FSGS, a disease with limited therapeutic options and no consensus guidelines for prevention or treatment. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT03763643, identifier NCT03763643.
Collapse
Affiliation(s)
- Michelle N. Rheault
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
| | - Sandra Amaral
- Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
| | - Margret Bock
- Department of Pediatrics, Children’s Hospital of Colorado, Denver, CO, United States
| | | | - Blanche Chavers
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
| | - Mireile El Ters
- Department of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - Rouba Garro
- Department of Pediatrics, Emory University, Atlanta, GA, United States
| | | | - Amit Govil
- Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Lyndsay Harshman
- Department of Pediatrics, University of Iowa, Iowa, IA, United States
| | - Hatem Amer
- Department of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States
| | - David K. Hooper
- Division of Nephrology and Hypertension, Cincinnati Children’s Hospital, Cincinnati, OH, United States
- Department of Pediatrics, University of Cincinnati, Cincinnati, OH, United States
| | - Ajay K. Israni
- The Kidney Center at Hennepin Healthcare, Hennepin Health, Minneapolis, MN, United States
- Department of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Samy Riad
- Department of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Junichiro Sageshima
- Department of Surgery, University of California, Davis, Davis, CA, United States
| | - Ron Shapiro
- Department of Surgery, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY, United States
| | - Michael Seifert
- Heersink School of Medicine, Department of Pediatrics, School of Medicine, University of Alabama, Birmingham, AL, United States
| | - Jodi Smith
- Department of Pediatrics, Seattle Children’s Hospital, Seattle, WA, United States
| | - Randall Sung
- Department of Surgery, University of Michigan Health, Ann, Arbor, MI, United States
| | - Christie P. Thomas
- Department of Internal Medicine, University of Iowa, Iowa City, IA, United States
| | - Qi Wang
- Clinical and Translational Science Institute, University of Minnesota, Minneapolis, MN, United States
| | - Priya S. Verghese
- Department of Pediatrics, Northwestern University, Ann & Robert H. Lurie Children’s Hospital, Chicago, IL, United States
| |
Collapse
|
|
38
|
Njeim R, Alkhansa S, Fornoni A. Unraveling the Crosstalk between Lipids and NADPH Oxidases in Diabetic Kidney Disease. Pharmaceutics 2023; 15:pharmaceutics15051360. [PMID: 37242602 DOI: 10.3390/pharmaceutics15051360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of end-stage renal disease. Abnormal lipid metabolism and intrarenal accumulation of lipids have been shown to be strongly correlated with the development and progression of diabetic kidney disease (DKD). Cholesterol, phospholipids, triglycerides, fatty acids, and sphingolipids are among the lipids that are altered in DKD, and their renal accumulation has been linked to the pathogenesis of the disease. In addition, NADPH oxidase-induced production of reactive oxygen species (ROS) plays a critical role in the development of DKD. Several types of lipids have been found to be tightly linked to NADPH oxidase-induced ROS production. This review aims to explore the interplay between lipids and NADPH oxidases in order to provide new insights into the pathogenesis of DKD and identify more effective targeted therapies for the disease.
Collapse
Affiliation(s)
- Rachel Njeim
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Sahar Alkhansa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
- AUB Diabetes, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| |
Collapse
|
|
39
|
Zhang J, Zhao H, Li X, Qian R, Gao P, Lu S, Ma Z. Efficacy of low-dose rituximab in minimal change disease and prevention of relapse. BMC Nephrol 2023; 24:112. [PMID: 37101300 PMCID: PMC10134665 DOI: 10.1186/s12882-023-03092-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 02/20/2023] [Indexed: 04/28/2023] Open
Abstract
BACKGROUND Minimal change disease (MCD) is a major cause of nephrotic syndrome (NS) in children and a minority of adults. The higher tendency to relapse put patients at risk for prolonged exposure to steroids and other immunosuppressive agents. B cell depletion with rituximab (RTX) may be beneficial to the treatment and prevention of frequently relapsing MCD. Therefore, this study aimed to verify the therapeutic/preventive effects of low-dose RTX on the relapse in adult with MCD. METHODS A total of 33 adult patients were selected for the study, including 22 patients with relapsing MCD in relapse treatment group who were treated with low-dose RTX (200 mg per week × 4 following by 200 mg every 6 months) and 11 patients in relapse prevention group with complete remission (CR) after steroid therapy were treated with RTX (200 mg ×1 every 6 months) for preventing the relapse of MCD. RESULTS Of the 22 patients with MCD in relapse treatment group, there were 21 cases (95.45%) of remission [2 (9.09%) partial remission (PR), 19 (86.36%) CR], 1 (4.56%) no remission (NR) and 20 (90.90%) relapse-free. The Median duration of sustained remission was 16.3 months (3, 23.5 months, inter quartile range (IQR)). 11 patients in the relapse prevention group during a follow-up of 12 months (9-31 months) had no relapse. The average dose of prednisone in two groups after RTX treatment was significantly lower than before treatment. CONCLUSION The results of this study suggested low-dose RTX can significantly reduce relapse rate and steroid dose in adults with MCD with fewer side effects. Low-dose RTX regimens may be beneficial for the treatment of relapsing MCD in adults and may be the preferred regimen for patients at high risk for the development of adverse events from corticosteroids.
Collapse
Affiliation(s)
- Jian Zhang
- Division of nephrology, Gansu Provincial Hospital, Lanzhou, 730001, China
| | - Hui Zhao
- Division of nephrology, Gansu Provincial Hospital, Lanzhou, 730001, China
| | - Xiaoli Li
- Division of nephrology, Gansu Provincial Hospital, Lanzhou, 730001, China
| | - Rui Qian
- Division of nephrology, Gansu Provincial Hospital, Lanzhou, 730001, China
| | - Peijuan Gao
- Division of nephrology, Gansu Provincial Hospital, Lanzhou, 730001, China
| | - Shouyan Lu
- Division of nephrology, Gansu Provincial Hospital, Lanzhou, 730001, China
| | - Zhigang Ma
- Department of nephrology, The Second Affiliated Hospital, School of Medcine, The Chinese University of Hong Kong, Longgang District People's Hospital of Shenzhen, Shenzhen, Guangdong, 518172, China.
| |
Collapse
|
|
40
|
Chan EYH, Yap DYH, Colucci M, Ma ALT, Parekh RS, Tullus K. Use of Rituximab in Childhood Idiopathic Nephrotic Syndrome. Clin J Am Soc Nephrol 2023; 18:533-548. [PMID: 36456193 PMCID: PMC10103321 DOI: 10.2215/cjn.08570722] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 10/11/2022] [Accepted: 10/31/2022] [Indexed: 12/04/2022]
Abstract
Rituximab is an established therapy in children with idiopathic nephrotic syndrome to sustain short- to medium-term disease remission and avoid steroid toxicities. Recent trials focus on its use as a first-line agent among those with milder disease severity. Rituximab is used in multidrug refractory nephrotic syndrome and post-transplant disease recurrence, although the evidence is much less substantial. Available data suggest that the treatment response to rituximab depends on various patient factors, dosing regimen, and the concomitant use of maintenance immunosuppression. After repeated treatments, patients are found to have an improving response overall with a longer relapse-free period. The drug effect, however, is not permanent, and 80% of patients eventually relapse and many will require an additional course of rituximab. This underpins the importance of understanding the long-term safety profile on repeated treatments. Although rituximab appears to be generally safe, there are concerns about long-term hypogammaglobulinemia, especially in young children. Reliable immunophenotyping and biomarkers are yet to be discovered to predict treatment success, risk of both rare and severe side effects, e.g. , persistent hypogammaglobulinemia, and guiding of redosing strategy. In this review, we highlight recent advances in the use of rituximab for childhood nephrotic syndrome and how the therapeutic landscape is evolving.
Collapse
Affiliation(s)
- Eugene Yu-hin Chan
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon, Hong Kong
- Department of Paediatric and Adolescent Medicine, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Desmond Yat-hin Yap
- Division of Nephrology, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong
| | - Manuela Colucci
- Renal Diseases Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Alison Lap-tak Ma
- Paediatric Nephrology Centre, Hong Kong Children's Hospital, Kowloon, Hong Kong
- Department of Paediatric and Adolescent Medicine, Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Rulan S. Parekh
- Departments of Medicine and Pediatrics, Women's College Hospital, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
| | - Kjell Tullus
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom
| |
Collapse
|
|
41
|
Kwon HE, Kim YH, Lee SA, Lee JJ, Ko Y, Shin S, Jung JH, Sung FS, Baek CH, Kim H, Park SK, Kwon H. Post-operative recurrence of focal segmental glomerulosclerosis according to pre-transplant treatment after kidney transplantation. BMC Nephrol 2023; 24:53. [PMID: 36922759 PMCID: PMC10018840 DOI: 10.1186/s12882-023-03098-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023] Open
Abstract
BACKGROUND Recurrent focal segmental glomerulosclerosis (FSGS) after kidney transplantation (KT) is a serious complication and a significant risk factor for graft failure. However, there is no clear evidence of the effectiveness of pre-transplant treatment using plasmapheresis (PP) or rituximab in preventing post-operative FSGS recurrence after KT. METHODS This single-center retrospective study included 99 adult patients with biopsy-proven primary FSGS who underwent KT between 2007 and 2018. The patients were divided into the pre-treatment group (N = 53, 53.5%) and no pre-treatment group (N = 46, 46.5%). In the pre-transplant group, prophylactic PP was administered before KT in patients undergoing living donor transplantation and the day after KT in those undergoing deceased donor transplantation. RESULTS The rate of immediate post-operative recurrence was significantly higher in the no pre-treatment group (16 [34.8%]) than in the pre-treatment group (5 [9.4%]; P = 0.002). There were three cases of graft failure due to recurrent FSGS, all of which were in the no pre-treatment group. After adjusting for possible confounding factors, age (per 10-year increase; OR = 0.61, CI, 0.42-0.90; P = 0.012) and pre-transplant treatment (vs. no pre-transplant treatment; OR = 0.17, CI, 0.05-0.54; P = 0.003) were identified as significant factors associated with FSGS recurrence. The rate of death-censored graft survival was significantly superior in the pretransplant treatment group (P = 0.042). CONCLUSION Pre-transplant treatment with PP was associated with beneficial effects on preventing FSGS recurrence after KT.
Collapse
Affiliation(s)
- Hye Eun Kwon
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, 05505, Seoul, Korea
| | - Young Hoon Kim
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, 05505, Seoul, Korea
| | - Sang Ah Lee
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, 05505, Seoul, Korea
| | - Jae Jun Lee
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, 05505, Seoul, Korea
| | - Youngmin Ko
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, 05505, Seoul, Korea
| | - Sung Shin
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, 05505, Seoul, Korea
| | - Joo Hee Jung
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, 05505, Seoul, Korea
| | - Frances S Sung
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, 05505, Seoul, Korea
| | - Chung Hee Baek
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyosang Kim
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Su-Kil Park
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyunwook Kwon
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, 05505, Seoul, Korea.
| |
Collapse
|
|
42
|
Burke GW, Chandar J, Sageshima J, Ortigosa-Goggins M, Amarapurkar P, Mitrofanova A, Defreitas MJ, Katsoufis CP, Seeherunvong W, Centeno A, Pagan J, Mendez-Castaner LA, Mattiazzi AD, Kupin WL, Guerra G, Chen LJ, Morsi M, Figueiro JMG, Vianna R, Abitbol CL, Roth D, Fornoni A, Ruiz P, Ciancio G, Garin EH. Benefit of B7-1 staining and abatacept for treatment-resistant post-transplant focal segmental glomerulosclerosis in a predominantly pediatric cohort: time for a reappraisal. Pediatr Nephrol 2023; 38:145-159. [PMID: 35507150 PMCID: PMC9747833 DOI: 10.1007/s00467-022-05549-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 02/28/2022] [Accepted: 03/15/2022] [Indexed: 01/10/2023]
Abstract
BACKGROUND Primary FSGS manifests with nephrotic syndrome and may recur following KT. Failure to respond to conventional therapy after recurrence results in poor outcomes. Evaluation of podocyte B7-1 expression and treatment with abatacept (a B7-1 antagonist) has shown promise but remains controversial. METHODS From 2012 to 2020, twelve patients developed post-KT FSGS with nephrotic range proteinuria, failed conventional therapy, and were treated with abatacept. Nine/twelve (< 21 years old) experienced recurrent FSGS; three adults developed de novo FSGS, occurring from immediately, up to 8 years after KT. KT biopsies were stained for B7-1. RESULTS Nine KTRs (75%) responded to abatacept. Seven of nine KTRs were B7-1 positive and responded with improvement/resolution of proteinuria. Two patients with rFSGS without biopsies resolved proteinuria after abatacept. Pre-treatment UPCR was 27.0 ± 20.4 (median 13, range 8-56); follow-up UPCR was 0.8 ± 1.3 (median 0.2, range 0.07-3.9, p < 0.004). Two patients who were B7-1 negative on multiple KT biopsies did not respond to abatacept and lost graft function. One patient developed proteinuria while receiving belatacept, stained B7-1 positive, but did not respond to abatacept. CONCLUSIONS Podocyte B7-1 staining in biopsies of KTRs with post-transplant FSGS identifies a subset of patients who may benefit from abatacept. A higher resolution version of the Graphical abstract is available as Supplementary information.
Collapse
Affiliation(s)
- George W. Burke
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, 1801 NW 9th Ave, Highland Professional Building, Miami, FL 33136 USA
| | - Jayanthi Chandar
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Junichiro Sageshima
- Division of Transplant Surgery, Department of Surgery, University of California Davis School of Medicine, Sacramento, CA 95817 USA
| | - Mariella Ortigosa-Goggins
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, and the Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Pooja Amarapurkar
- Division of Nephrology, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30309 USA
| | - Alla Mitrofanova
- Research, Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Marissa J. Defreitas
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Chryso P. Katsoufis
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Wacharee Seeherunvong
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Alexandra Centeno
- Transplant Clinical Pharmacy Services, Miami Transplant Institute, Jackson Memorial Hospital, Miami, FL 33136 USA
| | - Javier Pagan
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, and the Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Lumen A. Mendez-Castaner
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, and the Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Adela D. Mattiazzi
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, and the Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Warren L. Kupin
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, and the Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Giselle Guerra
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, and the Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Linda J. Chen
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, 1801 NW 9th Ave, Highland Professional Building, Miami, FL 33136 USA
| | - Mahmoud Morsi
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, 1801 NW 9th Ave, Highland Professional Building, Miami, FL 33136 USA
| | - Jose M. G. Figueiro
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, 1801 NW 9th Ave, Highland Professional Building, Miami, FL 33136 USA
| | - Rodrigo Vianna
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, 1801 NW 9th Ave, Highland Professional Building, Miami, FL 33136 USA ,Division of Liver and GI Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Carolyn L. Abitbol
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - David Roth
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, and the Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Phillip Ruiz
- Transplant Pathology, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL 33136 USA
| | - Gaetano Ciancio
- Division of Kidney-Pancreas Transplantation, Department of Surgery, Miami Transplant Institute, University of Miami Miller School of Medicine, 1801 NW 9th Ave, Highland Professional Building, Miami, FL 33136 USA
| | - Eduardo H. Garin
- Division of Nephrology, Department of Pediatrics, University of Florida School of Medicine, Gainesville, FL 32610 USA
| |
Collapse
|
|
43
|
Therapeutic trials in difficult to treat steroid sensitive nephrotic syndrome: challenges and future directions. Pediatr Nephrol 2023; 38:17-34. [PMID: 35482099 PMCID: PMC9048617 DOI: 10.1007/s00467-022-05520-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 02/07/2022] [Accepted: 02/24/2022] [Indexed: 01/10/2023]
Abstract
Steroid sensitive nephrotic syndrome is a common condition in pediatric nephrology, and most children have excellent outcomes. Yet, 50% of children will require steroid-sparing agents due to frequently relapsing disease and may suffer consequences from steroid dependence or use of steroid-sparing agents. Several steroid-sparing therapeutic agents are available with few high quality randomized controlled trials to compare efficacy leading to reliance on observational data for clinical guidance. Reported trials focus on short-term outcomes such as time to first relapse, relapse rates up to 1-2 years of follow-up, and few have studied long-term remission. Trial designs often do not consider inter-individual variability, and differing response to treatments may occur due to heterogeneity in pathogenic mechanisms, and genetic and environmental influences. Strategies are proposed to improve the quantity and quality of trials in steroid sensitive nephrotic syndrome with integration of biomarkers, novel trial designs, and standardized outcomes, especially for long-term remission. Collaborative efforts among international trial networks will help move us toward a shared goal of finding a cure for children with nephrotic syndrome.
Collapse
|
|
44
|
Aslam A, Koirala A. Review of the Role of Rituximab in the Management of Adult Minimal Change Disease and Immune-Mediated Focal and Segmental Glomerulosclerosis. GLOMERULAR DISEASES 2023; 3:211-219. [PMID: 37901702 PMCID: PMC10601923 DOI: 10.1159/000533695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 08/14/2023] [Indexed: 10/31/2023]
Abstract
Background Minimal change disease and primary FSGS are podocytopathies but are also immune-mediated diseases. Rituximab acts via multiple mechanisms by tilting the balance between autoreactive B and T cells in favor of regulatory B and T cells. The consequences are decreased production of cytokines, chemokines, and permeability factors by these cells. In the past decade, we have seen the discovery of autoantibodies mediating nephrotic syndrome (anti-annexin A2 antibody, anti-UCHL1 antibody, and anti-nephrin antibody), and rituximab decreases their production. Rituximab also binds to podocyte SMPDL3b and has direct podocyte actions. Summary Rituximab's role in managing these primary podocytopathies has been discussed in this brief review. Rituximab has been used extensively in children and adults with frequently relapsing and steroid-dependent nephrotic syndrome. However, rituximab is not very promising in adult steroid-resistant nephrotic syndrome. Although ofatumumab would cause prolonged B-cell depletion and is fully humanized, it is unclear if it is superior to rituximab in preventing relapse of nephrotic syndrome. Key Messages Rituximab therapy can induce prolonged remission in adults with frequently relapsing and steroid-dependent nephrotic syndrome. However, no good data exist on using rituximab in steroid-resistant nephrotic syndrome.
Collapse
Affiliation(s)
- Ahsan Aslam
- Division of Nephrology and Hypertension, Assistant Professor of Clinical Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Abbal Koirala
- Division of Nephrology, Clinical Assistant Professor of Medicine, University of Washington, Seattle, WA, USA
| |
Collapse
|
|
45
|
den Braanker DJW, Maas RJH, van Mierlo G, Parr NMJ, Bakker-van Bebber M, Deegens JKJ, Jansen PWTC, Gloerich J, Willemsen B, Dijkman HB, van Gool AJ, Wetzels JFM, Rinschen MM, Vermeulen M, Nijenhuis T, van der Vlag J. Primary Focal Segmental Glomerulosclerosis Plasmas Increase Lipid Droplet Formation and Perilipin-2 Expression in Human Podocytes. Int J Mol Sci 2022; 24:ijms24010194. [PMID: 36613637 PMCID: PMC9820489 DOI: 10.3390/ijms24010194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/13/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Many patients with primary focal segmental glomerulosclerosis (FSGS) develop recurrence of proteinuria after kidney transplantation. Several circulating permeability factors (CPFs) responsible for recurrence have been suggested, but were never validated. We aimed to find proteins involved in the mechanism of action of CPF(s) and/or potential biomarkers for the presence of CPF(s). Cultured human podocytes were exposed to plasma from patients with FSGS with presumed CPF(s) or healthy and disease controls. Podocyte proteomes were analyzed by LC-MS. Results were validated using flow cytometry, RT-PCR, and immunofluorescence. Podocyte granularity was examined using flow cytometry, electron microscopy imaging, and BODIPY staining. Perilipin-2 protein expression was increased in podocytes exposed to presumed CPF-containing plasmas, and correlated with the capacity of plasma to induce podocyte granularity, identified as lipid droplet accumulation. Elevated podocyte perilipin-2 was confirmed at protein and mRNA level and was also detected in glomeruli of FSGS patients whose active disease plasmas induced podocyte perilipin-2 and lipid droplets. Our study demonstrates that presumably, CPF-containing plasmas from FSGS patients induce podocyte lipid droplet accumulation and perilipin-2 expression, identifying perilipin-2 as a potential biomarker. Future research should address the mechanism underlying CPF-induced alterations in podocyte lipid metabolism, which ultimately may result in novel leads for treatment.
Collapse
Affiliation(s)
- Dirk J. W. den Braanker
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Rutger J. H. Maas
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Guido van Mierlo
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
| | - Naomi M. J. Parr
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Marinka Bakker-van Bebber
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Jeroen K. J. Deegens
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Pascal W. T. C. Jansen
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
| | - Jolein Gloerich
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Brigith Willemsen
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Henry B. Dijkman
- Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Alain J. van Gool
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Jack F. M. Wetzels
- Department of Nephrology, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Markus M. Rinschen
- Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Michiel Vermeulen
- Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands
- Oncode Institute, 3521 AL Utrecht, The Netherlands
| | - Tom Nijenhuis
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Correspondence:
| | - Johan van der Vlag
- Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| |
Collapse
|
|
46
|
Parkes JE, Boehler JF, Li N, Kendra RM, O'Hanlon TP, Hoffman EP, Peterson JM, Miller FW, Rider LG, Nagaraju K. A novel estrogen receptor 1-sphingomyelin phosphodiesterase acid like 3B pathway mediates rituximab response in myositis patients. Rheumatology (Oxford) 2022:6883897. [PMID: 36478205 PMCID: PMC10393434 DOI: 10.1093/rheumatology/keac687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 11/19/2022] [Accepted: 12/01/2022] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES The B cell depleting biologic, rituximab, is used to treat refractory autoimmune myositis. However, the beneficial effects of rituximab appear to outweigh the known contribution of B-cells in myositis. We aimed to elucidate how myositis patients respond differently to rituximab and possible alternative mechanisms of action. METHODS Here we have: a) comprehensively investigated concurrent mRNA and microRNA expression in muscle biopsies taken at baseline and 16 weeks post treatment in ten patients who were part of the rituximab in myositis (RIM) trial; and b) investigated the beneficial effect of rituximab on myositis muscle cells. RESULTS Our analyses identified an increased number of changes in gene expression in biopsies from patients who had a clinical response to rituximab (n = 5) compared with non-responders (n = 5). The two groups had completely different changes in microRNA and mRNA expression following rituximab therapy, with the exception of one mRNA, BHMT2. Networks of mRNA and microRNA with opposite direction of expression changes highlighted ESR1 as upregulated in responders. We confirmed ESR1 upregulation upon rituximab treatment of immortalized myotubes and primary human dermatomyositis muscle cells in vitro, demonstrating a direct effect of rituximab on muscle cells. Notably, despite showing a response to rituximab, human dermatomyositis primary muscle cells did not express the rituximab target, CD20. However, these cells expressed a possible alternative target of rituximab, sphingomyelinase-like phosphodiesterase 3 b (SMPDL3B). CONCLUSION In addition to B cell depletion, rituximab may be beneficial in myositis due to increased ESR1 signalling mediated by rituximab binding to SMPDL3B on skeletal muscle cells.
Collapse
Affiliation(s)
- Joanna E Parkes
- School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA
| | | | - Ning Li
- School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA
| | - Ryan M Kendra
- School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA
| | - Terrance P O'Hanlon
- Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Eric P Hoffman
- School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA
| | - Jennifer M Peterson
- School of Exercise & Rehabilitative Sciences, The University of Toledo, OH, USA
| | - Frederick W Miller
- Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Lisa G Rider
- Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Kanneboyina Nagaraju
- School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA
| |
Collapse
|
|
47
|
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
|
|
48
|
Sakr HI, Edrees B, Taher HO, Miliany TT, Gazzaz RY, AlRuwaithi AO, Alamer MF, Metawee ME. Combined Methylprednisolone Pulse Therapy plus Rituximab for Treating a Rare Juvenile Steroid-Resistant Nephrotic Syndrome with Cerebral Venous Sinus Thrombosis: A Case Report. J Cardiovasc Dev Dis 2022; 9:383. [PMID: 36354782 PMCID: PMC9692607 DOI: 10.3390/jcdd9110383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 10/03/2024] Open
Abstract
Background: Cerebral venous sinus thrombosis (CVST) secondary to nephrotic syndrome (NS) is rarely reported. Additionally, treating steroid-sensitive nephrotic syndrome (SSNS) that changes to steroid resistance (SRNS) is difficult, with many relapses and side effects. Case presentation: A 32-month-old SSNS male child turned into SRNS and developed cerebral venous sinus thrombosis (CVST), a rare complication of NS. As a result of the administration of combined pulse methylprednisolone and IV Rituximab (RTX) therapy, the patient showed marked improvement, the results of urine analysis were remarkably improved, and the child started to respond to treatment. Conclusion: Successful treatment of a rare case of juvenile SSNS behaving as SRNS with the development of CVST could be established using combined steroid pulse therapy, Enoxaparin, and the B lymphocytes monoclonal antibodies RTX.
Collapse
Affiliation(s)
- Hader I. Sakr
- Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo 11511, Egypt
- Medicine Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Burhan Edrees
- Department of Pediatrics, Umm Al-Qura University, Makkah 24451, Saudi Arabia
| | - Hussein Omar Taher
- Medicine Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Tuleen Talal Miliany
- Medicine Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Raneem Yasser Gazzaz
- Medicine Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Asma Omar AlRuwaithi
- Medicine Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Mohammed Fouad Alamer
- Medicine Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Mostafa E. Metawee
- Department of Histology and Cytology, Faculty of Medicine, Al-Azhar University, Cairo 11511, Egypt
| |
Collapse
|
|
49
|
Zuzda K, Grycuk W, Małyszko J, Małyszko J. Kidney and lipids: novel potential therapeutic targets for dyslipidemia in kidney disease? Expert Opin Ther Targets 2022; 26:995-1009. [PMID: 36548906 DOI: 10.1080/14728222.2022.2161887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Altered lipid distribution and metabolism may lead to the development and/or progression of chronic kidney disease (CKD). Dyslipidemia is a major risk factor for CKD and increases the risk of cardiovascular events and mortality. Therefore, lipid-lowering treatments may decrease cardiovascular risk and prevent death. AREAS COVERED Key players involved in regulating lipid accumulation in the kidney; contribution of lipids to CKD progression, lipotoxicity, and mitochondrial dysfunction in kidney disease; recent therapeutic approaches for dyslipidemia. EXPERT OPINION The precise mechanisms for regulating lipid metabolism, particularly in kidney disease, are poorly understood. Guidelines for lipid-lowering therapy for CKD are controversial. Several hypolipemic therapies are available, but compared to others, statin therapy is the most common. No clinical trial has evaluated the efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) in preventing cardiovascular events or improving kidney function among patients with CKD or kidney transplant recipients. Attractive alternatives, such as PCSK9-small interfering RNA (siRNA) molecules or evinacumab are available. Additionally, several promising agents, such as cyclodextrins and the FXR/TGR5 dual agonist, INT-767, can improve renal lipid metabolism disorders and delay CKD progression. Drugs targeting mitochondrial dysfunction could be an option for the treatment of dyslipidemia and lipotoxicity, particularly in renal diseases.
Collapse
Affiliation(s)
- Konrad Zuzda
- Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, Bialystok, Poland
| | - Wiktoria Grycuk
- Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, Bialystok, Poland
| | - Jacek Małyszko
- 1st Department of Nephrology and Transplantology, Medical University of Bialystok, Bialystok, Poland
| | - Jolanta Małyszko
- Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, Bialystok, Poland
| |
Collapse
|
|
50
|
Liu J, Guan F. B cell phenotype, activity, and function in idiopathic nephrotic syndrome. Pediatr Res 2022:10.1038/s41390-022-02336-w. [PMID: 36316536 DOI: 10.1038/s41390-022-02336-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 09/14/2022] [Accepted: 09/20/2022] [Indexed: 11/05/2022]
Abstract
Idiopathic nephrotic syndrome (INS) is the most frequent glomerular disease in childhood. However, its underlying etiology mechanism lacks thorough understanding. Previous studies have described INS as a T cell functional disorder resulting in increased plasma lymphocyte-derived permeability factors. In children with frequent relapses of nephrotic syndrome, the mechanism underlying the therapeutic efficacy of CD20 monoclonal antibodies in depleting B cells may provide additional evidence in exploring the critical role of B lymphocytes in INS pathogenesis. Previous studies have proposed that RTX bound to CD20 through antibody-dependent and complement-dependent cytotoxicity and led to lytic clearance of B cells. Additionally, RTX exerted an effect by blocking the interaction between B and T cells or regulating homeostasis and functions of T cell subsets. Recent studies on the development, differentiation, and activation of B-lymphocytes in glomerular diseases have suggested that the B-lymphocytes participate in the INS pathogenesis through interaction with T cells, secretion of antibodies, or production of cytokines. In this study, we aimed to provide a detailed description of the current knowledge on the development, differentiation, activity, functions, and related regulating factors of B cells involved in INS. Thus, further understanding of the immunopathogenesis of INS may offer some opportunities in precisely targeting B cells during therapeutic interventions. IMPACT: The topic "B cells play a role in glomerular disease" is a novel point, which is not completely described previously. We described interactions between T and B cells and immunoglobulin, IgG, IgM, IgE, etc. as well in glomerular disease. The research of regulatory factors associated with B cell's function, like BAFF, is a hot topic in other diseases; however, it is rare in glomerular disease.
Collapse
Affiliation(s)
- Junhan Liu
- Department of Pediatrics, Affiliated Hospital of Xuzhou Medical University, 221002, Xuzhou, Jiangsu, China
| | - Fengjun Guan
- Department of Pediatrics, Affiliated Hospital of Xuzhou Medical University, 221002, Xuzhou, Jiangsu, China.
| |
Collapse
|