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Kaneko K. Gut dysbiosis as a susceptibility factor in childhood idiopathic nephrotic syndrome. Pediatr Neonatol 2025; 66 Suppl 1:S2-S7. [PMID: 39521679 DOI: 10.1016/j.pedneo.2024.10.003] [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] [Indexed: 11/16/2024] Open
Abstract
Idiopathic nephrotic syndrome (INS) is a relatively common renal disorder of childhood characterized by severe proteinuria and associated hypoproteinemia and edema. Although the pathogenesis of INS remains unknown, the prevailing theory of its pathogenesis is as follows. Antigenic stimulation, such as viral infections or vaccines, in children with susceptibility factors for INS triggers abnormal immune responses, resulting in production of pathogenic substances that injure podocytes (renal glomerular epithelial cells). The injured podocytes then change their function and morphology, resulting in increased permeability of plasma proteins. Consequently, plasma proteins, especially albumin, are leaked into urine and massive proteinuria ensues. Research on susceptibility factors for INS has focused on polymorphisms in several genes including human leukocyte antigen class II genes. However, we propose that dysbiosis of the intestinal microbiota could be a susceptibility factor for relapse. This proposal is based on our research group finding that children with INS and frequent relapses have gut dysbiosis characterized by a decreased proportion of beneficial bacteria such as short-chain fatty acid-producing bacteria. Dysbiosis from the neonatal period to infancy may result from environmental factors, such as cesarean section delivery and antibiotic administration, which prevent the establishment of a normal intestinal microbiota. Dysbiosis leads to aberrant gut immunity and is characterized by a decreased ratio of T helper 1 cells/T helper 2 cells and an increased ratio of T helper 17 cells/regulatory T-cells. Therefore, relapse occurs when immunologically pathogenic factors that injure podocytes are produced in response to trigger events in children with INS and gut dysbiosis. Our recent clinical trial suggested that long-term oral administration of butyric acid-producing bacterium as a probiotic is promising for suppressing relapse. Therefore, studying the causal relationship between dysbiosis and relapses in patients with INS in a larger number of patients is necessary.
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Affiliation(s)
- Kazunari Kaneko
- Department of Pediatrics, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka, 573 1010, Japan.
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Srivastava T, Sharma M. Emerging Role of SH3BP2 as Regulator of Immune and Nonimmune Cells in Nephrotic Syndrome. GLOMERULAR DISEASES 2025; 5:1-12. [PMID: 39991193 PMCID: PMC11842026 DOI: 10.1159/000542703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/17/2024] [Indexed: 02/25/2025]
Abstract
Background Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are major forms of nephrotic syndrome that remain difficult to treat. MCD and FSGS have distinct but also overlapping clinical, histological, metabolic, and molecular features. Effective use of immunosuppressive drugs, activated immune cells, altered cytokine profiles, and upregulated signaling pathways suggest a link between immune dysfunction and nephrotic syndrome, but the exact mechanism of immunopathogenesis is unclear. Immune dysfunction is an area of ongoing research for identifying novel molecular targets for treating nephrotic syndrome. However, the available animal models do not directly address the role of immune dysfunction in nephrotic syndrome. Summary Genetic analysis indicates that heterogeneous genes related to the podocyte-specific proteins may indirectly cause damage to filtration barrier and influence the onset and progression of nephrotic syndrome. SH3BP2 protein regulates several pathways through its role as a scaffold for many signaling mediators and enzymes. SH3BP2 is expressed in immune as well as in nonimmune cells including podocytes. The role of SH3BP2 is discussed in the context of cells and molecules of adaptive and innate immune systems. Available information on the importance of SH3BP2 in diseases other than nephrotic syndrome and its role in the immunopathogenesis of human nephrotic syndrome are summarized. We outline the key features of a transgenic mouse strain with a gain-in-function mutation (Sh3bp2 KI/KI ) as a potential model to study immunopathogenesis of nephrotic syndrome. Key Messages Non-receptor, non-catalytic proteins such as SH3BP2 are a novel group of proteins that regulate the innate and adaptive immune responses in nephrotic syndrome. New evidence suggests a critical role of SH3BP2 in immunopathogenesis of nephrotic syndrome. Our recent results demonstrate that transgenic mice (Sh3bp2 KI/KI ) with a gain-in-function mutation will likely be a unique model to study immunopathogenesis of nephrotic syndrome.
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Affiliation(s)
- Tarak Srivastava
- Section of Nephrology, Children’s Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, USA
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Mukut Sharma
- Kansas City VA Medical Center, Kansas City, MO, USA
- Midwest Veterans’ Biomedical Research Foundation (MVBRF), Kansas City, MO, USA
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Regalia A, Abinti M, Alfieri CM, Campise M, Verdesca S, Zanoni F, Castellano G. Post-transplant glomerular diseases: update on pathophysiology, risk factors and management strategies. Clin Kidney J 2024; 17:sfae320. [PMID: 39664990 PMCID: PMC11630810 DOI: 10.1093/ckj/sfae320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Indexed: 12/13/2024] Open
Abstract
In recent years, advancements in immunosuppressive medications and post-transplant management have led to a significant decrease in acute rejection rates in renal allografts and consequent improvement in short-term graft survival. In contrast, recent data have shown an increased incidence of post-transplant glomerular diseases, which currently represent a leading cause of allograft loss. Although pathogenesis is not fully understood, growing evidence supports the role of inherited and immunological factors and has identified potential pre- and post-transplant predictors. In this review, we illustrate recent advancements in the pathogenesis of post-transplant glomerular disease and the role of risk factors and immunological triggers. In addition, we discuss potential prevention and management strategies.
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Affiliation(s)
- Anna Regalia
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Matteo Abinti
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
- Post-Graduate School of Specialization in Nephrology, University of Milan, Milan, Italy
| | - Carlo Maria Alfieri
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Mariarosaria Campise
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Simona Verdesca
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesca Zanoni
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giuseppe Castellano
- Department of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
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Finn LS. Nephrotic Syndrome Throughout Childhood: Diagnosing Podocytopathies From the Womb to the Dorm. Pediatr Dev Pathol 2024; 27:426-458. [PMID: 38745407 DOI: 10.1177/10935266241242669] [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] [Indexed: 05/16/2024]
Abstract
The etiologies of podocyte dysfunction that lead to pediatric nephrotic syndrome (NS) are vast and vary with age at presentation. The discovery of numerous novel genetic podocytopathies and the evolution of diagnostic technologies has transformed the investigation of steroid-resistant NS while simultaneously promoting the replacement of traditional morphology-based disease classifications with a mechanistic approach. Podocytopathies associated with primary and secondary steroid-resistant NS manifest as diffuse mesangial sclerosis, minimal change disease, focal segmental glomerulosclerosis, and collapsing glomerulopathy. Molecular testing, once an ancillary option, has become a vital component of the clinical investigation and when paired with kidney biopsy findings, provides data that can optimize treatment and prognosis. This review focuses on the causes including selected monogenic defects, clinical phenotypes, histopathologic findings, and age-appropriate differential diagnoses of nephrotic syndrome in the pediatric population with an emphasis on podocytopathies.
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Affiliation(s)
- Laura S Finn
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at The University of Pennsylvania, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
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Lemberg K, Mertens ND, Yousef K, Schneider R, Merz LM, Mansour B, Salmanullah D, Kolvenbach CM, Saida K, Yu S, Hölzel S, Steinsapir A, Goncalves KA, Nicolas Frank C, Franken GAC, Shril S, Buerger F, Hildebrandt F. Quantifiable and reproducible phenotypic assessment of a constitutive knockout mouse model for congenital nephrotic syndrome of the Finnish type. Sci Rep 2024; 14:15916. [PMID: 38987283 PMCID: PMC11237045 DOI: 10.1038/s41598-024-64883-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: 01/19/2024] [Accepted: 06/13/2024] [Indexed: 07/12/2024] Open
Abstract
Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of childhood chronic kidney disease. Congenital nephrotic syndrome of the Finnish type (CNF) (MIM# 256300) is caused by biallelic variants in the gene NPHS1, encoding nephrin, an integral component of the kidney filtration barrier. No causal treatments exist, and children inevitably require kidney replacement therapy. In preparation for gene replacement therapy (GRT) in CNF, we established a quantifiable and reproducible phenotypic assessment of the nephrin-deficient CNF mouse model: 129/Sv-Nphs1tm1Rkl/J. We assessed the phenotypic spectrum of homozygous mice (Nphs1tm1Rkl/Nphs1tm1Rkl) compared to heterozygous controls (Nphs1tm1Rkl/Nphs1WT) by the following parameters: 1. cohort survival, 2. podocyte foot process (FP) density per glomerular basement membrane (GBM) using transmission electron microscopy, 3. tubular microcysts in brightfield microscopy, and 4. urinary albumin/creatinine ratios. Nphs1tm1Rkl/Nphs1tm1Rkl mice exhibited: 1. perinatal lethality with median survival of 1 day, 2. FP effacement with median FP density of 1.00 FP/µm GBM (2.12 FP/µm in controls), 3. tubular dilation with 65 microcysts per section (6.5 in controls), and 4. increased albumin/creatinine ratio of 238 g/g (4.1 g/g in controls). We here established four quantifiable phenotyping features of a CNF mouse model to facilitate future GRT studies by enabling sensitive detection of phenotypic improvements.
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Affiliation(s)
- Katharina Lemberg
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Nils D Mertens
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kirollos Yousef
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ronen Schneider
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Lea M Merz
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Department of Pediatrics, University Hospital Leipzig, Leipzig, Germany
| | - Bshara Mansour
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Daanya Salmanullah
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Caroline M Kolvenbach
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Medical Faculty, Institute of Anatomy, University of Bonn, Bonn, Germany
| | - Ken Saida
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Seyoung Yu
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Selina Hölzel
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Andrew Steinsapir
- Deerfield Discovery and Development, Deerfield Management Company, L.P. (Series C), New York, NY, USA
| | - Kevin A Goncalves
- Deerfield Discovery and Development, Deerfield Management Company, L.P. (Series C), New York, NY, USA
| | - Camille Nicolas Frank
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Gijs A C Franken
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Shirlee Shril
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Florian Buerger
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- University Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Friedhelm Hildebrandt
- Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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Caparali EB, De Gregorio V, Barua M. Genetic Causes of Nephrotic Syndrome and Focal and Segmental Glomerulosclerosis. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:309-316. [PMID: 39084756 DOI: 10.1053/j.akdh.2024.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 03/29/2024] [Accepted: 04/01/2024] [Indexed: 08/02/2024]
Abstract
The field of nephrology has a long-standing interest in deciphering the genetic basis of nephrotic syndrome (NS), motivated by the mechanistic insights it provides in chronic kidney disease. The initial era of genetic studies solidified NS and the focal segmental glomerulosclerosis lesion as podocyte disorders. The likelihood of identifying a single gene (called monogenic) cause is higher if certain factors are present such as positive family history. Obtaining a monogenic diagnosis enables reproductive counseling and screening of family members. Now, with a new era of genomic studies facilitated by technological advances and the emergence of large genetically characterized cohorts, more insights are apparent. This includes the phenotypic breadth associated with disease genes, as evidenced in Alport syndrome and congenital NS of the Finnish type. Moreover, the underlying genetic architecture is more complex than previously appreciated, as shown by genome-wide association studies, suggesting that variants in multiple genes collectively influence risk. Achieving molecularly informed diagnoses also holds substantial potential for personalizing medicine, including the development of targeted therapeutics. Illustrative examples include coenzyme Q10 for ADCK4-associated NS and inaxaplin, a small molecule that inhibits apolipoprotein L1 channel activity, though larger studies are required to confirm benefit.
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Affiliation(s)
- Emine Bilge Caparali
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Vanessa De Gregorio
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Moumita Barua
- Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
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Koehler S, Hengel FE, Dumoulin B, Damashek L, Holzman LB, Susztak K, Huber TB. The 14th International Podocyte Conference 2023: from podocyte biology to glomerular medicine. Kidney Int 2024; 105:935-952. [PMID: 38447880 DOI: 10.1016/j.kint.2024.01.042] [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: 10/30/2023] [Revised: 12/11/2023] [Accepted: 01/02/2024] [Indexed: 03/08/2024]
Abstract
The 14th International Podocyte Conference took place in Philadelphia, Pennsylvania, USA from May 23 to 26, 2023. It commenced with an early-career researchers' meeting on May 23, providing young scientists with a platform to present and discuss their research findings. Throughout the main conference, 29 speakers across 9 sessions shared their insights on podocyte biology, glomerular medicine, novel technologic advancements, and translational approaches. Additionally, the event featured 3 keynote lectures addressing engineered chimeric antigen receptor T cell- and mRNA-based therapies and the use of biobanks for enhanced disease comprehension. Furthermore, 4 brief oral abstract sessions allowed scientists to present their findings to a broad audience. The program also included a panel discussion addressing the challenges of conducting human research within the American Black community. Remarkably, after a 5-year hiatus from in-person conferences, the 14th International Podocyte Conference successfully convened scientists from around the globe, fostering the presentation and discussion of crucial research findings, as summarized in this review. Furthermore, to ensure continuous and sustainable education, research, translation, and trial medicine related to podocyte and glomerular diseases for the benefit of patients, the International Society of Glomerular Disease was officially launched during the conference.
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Affiliation(s)
- Sybille Koehler
- III. Department of Medicine and Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Felicitas E Hengel
- III. Department of Medicine and Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
| | - Bernhard Dumoulin
- III. Department of Medicine and Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Laurel Damashek
- International Society of Glomerular Disease, Florence, Massachusetts, USA
| | - Lawrence B Holzman
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Katalin Susztak
- Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA; Institute of Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Tobias B Huber
- III. Department of Medicine and Hamburg Center for Kidney Health (HCKH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany; International Society of Glomerular Disease, Florence, Massachusetts, USA.
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Horinouchi T, Nagano C, Watts AJB. Anti-nephrin antibodies in steroid-sensitive nephrotic syndrome in Japanese children. Pediatr Nephrol 2024; 39:337. [PMID: 37495741 DOI: 10.1007/s00467-023-06107-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 07/28/2023]
Affiliation(s)
- Tomoko Horinouchi
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
| | - China Nagano
- Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
- Department of Medicine/Pediatric Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Andrew J B Watts
- Department of Medicine/Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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Boyer O, Dorval G. Multipopulation genome-wide association meta-analysis in pediatric steroid-sensitive nephrotic syndrome. Kidney Int 2024; 105:14-17. [PMID: 37714428 DOI: 10.1016/j.kint.2023.08.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/09/2023] [Indexed: 09/17/2023]
Affiliation(s)
- Olivia Boyer
- Néphrologie Pédiatrique, Centre de Référence du Syndrome Néphrotique Idiopathique de l'Enfant et l'Adulte, Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (APHP), INSERM U1163, Institut Imagine, Université Paris Cité, Paris, France.
| | - Guillaume Dorval
- Service de Médecine Génomique des Maladies Rares, Centre de Référence MAladies REnales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris (APHP), INSERM U1163, Institut Imagine, Université Paris Cité, Paris, France
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Cason RK, Chambers E, Tu T, Chryst-Stangl M, Huggins K, Lane BM, Ochoa A, Jackson AM, Gbadegesin RA. Genetic risk variants for childhood nephrotic syndrome and corticosteroid response. Front Pediatr 2023; 11:1248733. [PMID: 37868272 PMCID: PMC10588181 DOI: 10.3389/fped.2023.1248733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 09/22/2023] [Indexed: 10/24/2023] Open
Abstract
Introduction The etiology of most cases of nephrotic syndrome (NS) remains unknown, therefore patients are phenotypically categorized based on response to corticosteroid therapy as steroid sensitive NS (SSNS), or steroid resistant NS (SRNS). Genetic risk factors have been identified for SSNS from unbiased genome-wide association studies (GWAS), however it is unclear if these loci are disease risk loci in other forms of NS such as SRNS. Additionally, it remains unknown if these risk loci are associated with response to therapy. Thus, we investigated the association between SSNS risk loci and therapy response in a large, multi-race cohort of children along the entire spectrum of childhood-onset NS. Methods We enrolled 1,000 patients with childhood-onset NS comprised of SSNS and SRNS. Genotyping was done using TaqMan and Direct Sanger Sequencing for 9 previously reported childhood SSNS risk loci. We compared the allele frequencies (AF) and variant burden between NS vs. controls and SRNS vs. SSNS. Results All 9 risk loci were associated with NS compared with healthy controls (p = 3.5 × 10-3-<2.2 × 10-16). Variant burden greater than 7 was associated with risk of SRNS (OR 7.4, 95% CI 4.6-12.0, p = 8.2 × 10-16). Conclusion Our study showed that genetic risk loci for childhood SSNS are associated with pattern of therapy response, may help predict disease outcome, and set the stage for individualized treatment of NS.
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Affiliation(s)
- Rachel K. Cason
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC, United States
| | - Eileen Chambers
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC, United States
| | - Tiffany Tu
- Computational Biology and Bioinformatics Program, Duke Center for Statistical Genetics and Genomics, and Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, United States
| | - Megan Chryst-Stangl
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC, United States
| | - Kinsie Huggins
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC, United States
| | - Brandon M. Lane
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC, United States
| | - Alejandro Ochoa
- Computational Biology and Bioinformatics Program, Duke Center for Statistical Genetics and Genomics, and Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, United States
| | - Annette M. Jackson
- Department of Surgery, Duke University Medical Center, Durham, NC, United States
| | - Rasheed A. Gbadegesin
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC, United States
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Downie ML, Gupta S, Voinescu C, Levine AP, Sadeghi-Alavijeh O, Dufek-Kamperis S, Cao J, Christian M, Kari JA, Thalgahagoda S, Ranawaka R, Abeyagunawardena A, Gbadegesin R, Parekh R, Kleta R, Bockenhauer D, Stanescu HC, Gale DP. Common Risk Variants in AHI1 Are Associated With Childhood Steroid Sensitive Nephrotic Syndrome. Kidney Int Rep 2023; 8:1562-1574. [PMID: 37547536 PMCID: PMC10403666 DOI: 10.1016/j.ekir.2023.05.018] [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: 02/03/2023] [Revised: 04/21/2023] [Accepted: 05/22/2023] [Indexed: 08/08/2023] Open
Abstract
Introduction Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of kidney disease in children worldwide. Genome-wide association studies (GWAS) have demonstrated the association of SSNS with genetic variation at HLA-DQ/DR and have identified several non-HLA loci that aid in further understanding of disease pathophysiology. We sought to identify additional genetic loci associated with SSNS in children of Sri Lankan and European ancestry. Methods We conducted a GWAS in a cohort of Sri Lankan individuals comprising 420 pediatric patients with SSNS and 2339 genetic ancestry matched controls obtained from the UK Biobank. We then performed a transethnic meta-analysis with a previously reported European cohort of 422 pediatric patients and 5642 controls. Results Our GWAS confirmed the previously reported association of SSNS with HLA-DR/DQ (rs9271602, P = 1.12 × 10-27, odds ratio [OR] = 2.75). Transethnic meta-analysis replicated these findings and identified a novel association at AHI1 (rs2746432, P = 2.79 × 10-8, OR = 1.37), which was also replicated in an independent South Asian cohort. AHI1 is implicated in ciliary protein transport and immune dysregulation, with rare variation in this gene contributing to Joubert syndrome type 3. Conclusions Common variation in AHI1 confers risk of the development of SSNS in both Sri Lankan and European populations. The association with common variation in AHI1 further supports the role of immune dysregulation in the pathogenesis of SSNS and demonstrates that variation across the allele frequency spectrum in a gene can contribute to disparate monogenic and polygenic diseases.
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Affiliation(s)
- Mallory L. Downie
- Department of Renal Medicine, University College London, London, UK
- Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Sanjana Gupta
- Department of Renal Medicine, University College London, London, UK
| | - Catalin Voinescu
- Department of Renal Medicine, University College London, London, UK
| | - Adam P. Levine
- Department of Pathology, University College London, London, UK
| | | | | | - Jingjing Cao
- Division of Nephrology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Canada
| | | | - Jameela A. Kari
- Pediatric Nephrology Centre of Excellence, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
| | | | - Randula Ranawaka
- Department of Pediatrics, University of Peradeniya, Peradeniya, Sri Lanka
| | | | - Rasheed Gbadegesin
- Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA
| | - Rulan Parekh
- Division of Nephrology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Canada
- Department of Medicine, Women’s College Hospital, Toronto, Canada
| | - Robert Kleta
- Department of Renal Medicine, University College London, London, UK
- Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Detlef Bockenhauer
- Department of Renal Medicine, University College London, London, UK
- Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | | | - Daniel P. Gale
- Department of Renal Medicine, University College London, London, UK
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Vincenti F, Angeletti A, Ghiggeri GM. State of the art in childhood nephrotic syndrome: concrete discoveries and unmet needs. Front Immunol 2023; 14:1167741. [PMID: 37503337 PMCID: PMC10368981 DOI: 10.3389/fimmu.2023.1167741] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/21/2023] [Indexed: 07/29/2023] Open
Abstract
Nephrotic syndrome (NS) is a clinical entity characterized by proteinuria, hypoalbuminemia, and peripheral edema. NS affects about 2-7 per 100,000 children aged below 18 years old yearly and is classified, based on the response to drugs, into steroid sensitive (SSNS), steroid dependent, (SDNS), multidrug dependent (MDNS), and multidrug resistant (MRNS). Forms of NS that are more difficult to treat are associated with a worse outcome with respect to renal function. In particular, MRNS commonly progresses to end stage renal failure requiring renal transplantation, with recurrence of the original disease in half of the cases. Histological presentations of NS may vary from minimal glomerular lesions (MCD) to focal segmental glomerulosclerosis (FSGS) and, of relevance, the histological patterns do not correlate with the response to treatments. Moreover, around half of MRNS cases are secondary to causative pathogenic variants in genes involved in maintaining the glomerular structure. The pathogenesis of NS is still poorly understood and therapeutic approaches are mostly based on clinical experience. Understanding of pathogenetic mechanisms of NS is one of the 'unmet needs' in nephrology and represents a significant challenge for the scientific community. The scope of the present review includes exploring relevant findings, identifying unmet needs, and reviewing therapeutic developments that characterize NS in the last decades. The main aim is to provide a basis for new perspectives and mechanistic studies in NS.
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Affiliation(s)
- Flavio Vincenti
- Division of Nephrology, Department of Medicine and Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Andrea Angeletti
- Nephrology Dialysis and Transplantation, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
| | - Gian Marco Ghiggeri
- Nephrology Dialysis and Transplantation, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
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13
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Williams AE, Esezobor CI, Lane BM, Gbadegesin RA. Hiding in plain sight: genetics of childhood steroid-resistant nephrotic syndrome in Sub-Saharan Africa. Pediatr Nephrol 2023; 38:2003-2012. [PMID: 36459247 PMCID: PMC10416081 DOI: 10.1007/s00467-022-05831-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 11/14/2022] [Accepted: 11/14/2022] [Indexed: 12/03/2022]
Abstract
Steroid-resistant nephrotic syndrome (SRNS) is the most severe form of childhood nephrotic syndrome with an increased risk of progression to chronic kidney disease stage 5. Research endeavors to date have identified more than 80 genes that are associated with SRNS. Most of these genes regulate the structure and function of the podocyte, the visceral epithelial cells of the glomerulus. Although individuals of African ancestry have the highest prevalence of SRNS, especially those from Sub-Saharan Africa (SSA), with rates as high as 30-40% of all cases of nephrotic syndrome, studies focusing on the characterization and understanding of the genetic basis of SRNS in the region are negligible compared with Europe and North America. Therefore, it remains unclear if some of the variants in SRNS genes that are deemed pathogenic for SRNS are truly disease causing, and if the leading causes of monogenic nephrotic syndrome in other populations are the same for children in SSA with SRNS. Other implications of this lack of genetic data for SRNS in the region include the exclusion of children from the region from clinical trials aimed at identifying potential novel therapeutic agents for this severe form of nephrotic syndrome. This review underlines a need for concerted efforts to advance the genetic basis of SRNS in children in SSA. Such endeavors will complement global efforts at understanding the genetic basis of nephrotic syndrome.
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Affiliation(s)
- Anna Elizabeth Williams
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC, 27710, USA
| | - Christopher I Esezobor
- Department of Pediatrics, Faculty of Clinical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria
| | - Brandon M Lane
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC, 27710, USA
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - Rasheed A Gbadegesin
- Department of Pediatrics, Division of Nephrology, Duke University Medical Center, Durham, NC, 27710, USA.
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
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14
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Downie ML, Gupta S, Chan MMY, Sadeghi-Alavijeh O, Cao J, Parekh RS, Diz CB, Bierzynska A, Levine AP, Pepper RJ, Stanescu H, Saleem MA, Kleta R, Bockenhauer D, Koziell AB, Gale DP. Shared genetic risk across different presentations of gene test-negative idiopathic nephrotic syndrome. Pediatr Nephrol 2023; 38:1793-1800. [PMID: 36357634 PMCID: PMC10154254 DOI: 10.1007/s00467-022-05789-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 10/14/2022] [Accepted: 10/14/2022] [Indexed: 11/12/2022]
Abstract
BACKGROUND Idiop athic nephrotic syndrome (INS) is classified in children according to response to initial corticosteroid therapy into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS), and in adults according to histology into minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). However, there is well-recognised phenotypic overlap between these entities. Genome-wide association studies (GWAS) have shown a strong association between SSNS and variation at HLA, suggesting an underlying immunological basis. We sought to determine whether a risk score generated from genetic variants associated with SSNS could be used to gain insight into the pathophysiology of INS presenting in other ways. METHODS We developed an SSNS genetic risk score (SSNS-GRS) from the five variants independently associated with childhood SSNS in a previous European GWAS. We quantified SSNS-GRS in independent cohorts of European individuals with childhood SSNS, non-monogenic SRNS, MCD, and FSGS, and contrasted them with SSNS-GRS quantified in individuals with monogenic SRNS, membranous nephropathy (a different immune-mediated disease-causing nephrotic syndrome), and healthy controls. RESULTS The SSNS-GRS was significantly elevated in cohorts with SSNS, non-monogenic SRNS, MCD, and FSGS compared to healthy participants and those with membranous nephropathy. The SSNS-GRS in all cohorts with non-monogenic INS were also significantly elevated compared to those with monogenic SRNS. CONCLUSIONS The shared genetic risk factors among patients with different presentations of INS strongly suggests a shared autoimmune pathogenesis when monogenic causes are excluded. Use of the SSNS-GRS, in addition to testing for monogenic causes, may help to classify patients presenting with INS. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Mallory L Downie
- Department of Renal Medicine, University College London, 1st Floor, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK
- Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Sanjana Gupta
- Department of Renal Medicine, University College London, 1st Floor, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK
| | - Melanie M Y Chan
- Department of Renal Medicine, University College London, 1st Floor, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK
| | - Omid Sadeghi-Alavijeh
- Department of Renal Medicine, University College London, 1st Floor, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK
| | - Jingjing Cao
- Department of Medicine, Women's College Hospital, Toronto, Canada
| | - Rulan S Parekh
- Department of Medicine, Women's College Hospital, Toronto, Canada
- Department of Pediatrics, Division of Nephrology, The Hospital for Sick Children, Toronto, Canada
| | - Carmen Bugarin Diz
- Department of Paediatric Nephrology, Evelina London and Faculty of Life Sciences, King's College London, London, UK
| | - Agnieszka Bierzynska
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Adam P Levine
- Research Department of Pathology, University College London, London, UK
| | - Ruth J Pepper
- Department of Renal Medicine, University College London, 1st Floor, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK
| | - Horia Stanescu
- Department of Renal Medicine, University College London, 1st Floor, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK
| | - Moin A Saleem
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Robert Kleta
- Department of Renal Medicine, University College London, 1st Floor, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK
- Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Detlef Bockenhauer
- Department of Renal Medicine, University College London, 1st Floor, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK
- Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Ania B Koziell
- Department of Paediatric Nephrology, Evelina London and Faculty of Life Sciences, King's College London, London, UK
| | - Daniel P Gale
- Department of Renal Medicine, University College London, 1st Floor, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK.
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15
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Barry A, McNulty MT, Jia X, Gupta Y, Debiec H, Luo Y, Nagano C, Horinouchi T, Jung S, Colucci M, Ahram DF, Mitrotti A, Sinha A, Teeninga N, Jin G, Shril S, Caridi G, Bodria M, Lim TY, Westland R, Zanoni F, Marasa M, Turudic D, Giordano M, Gesualdo L, Magistroni R, Pisani I, Fiaccadori E, Reiterova J, Maringhini S, Morello W, Montini G, Weng PL, Scolari F, Saraga M, Tasic V, Santoro D, van Wijk JAE, Milošević D, Kawai Y, Kiryluk K, Pollak MR, Gharavi A, Lin F, Simœs E Silva AC, Loos RJF, Kenny EE, Schreuder MF, Zurowska A, Dossier C, Ariceta G, Drozynska-Duklas M, Hogan J, Jankauskiene A, Hildebrandt F, Prikhodina L, Song K, Bagga A, Cheong H, Ghiggeri GM, Vachvanichsanong P, Nozu K, Lee D, Vivarelli M, Raychaudhuri S, Tokunaga K, Sanna-Cherchi S, Ronco P, Iijima K, Sampson MG. Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome. Nat Commun 2023; 14:2481. [PMID: 37120605 PMCID: PMC10148875 DOI: 10.1038/s41467-023-37985-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 04/10/2023] [Indexed: 05/01/2023] Open
Abstract
Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.
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Affiliation(s)
- Alexandra Barry
- Division of Nephrology, Boston Children's Hospital, Boston, MA, USA
- Kidney Disease Initiative & Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Michelle T McNulty
- Division of Nephrology, Boston Children's Hospital, Boston, MA, USA
- Kidney Disease Initiative & Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Xiaoyuan Jia
- Genome Medical Science Project (Toyama), National Center for Global Health and Medicine (NCGM), Tokyo, Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yask Gupta
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Hanna Debiec
- Sorbonne Université, UPMC Paris 06, Institut National de la Santé et de la Recherde Médicale, Unité Mixte de Rechereche, S 1155, Paris, France
| | - Yang Luo
- Kennedy Institute of Rheumatology, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7FY, United Kingdom
- Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - China Nagano
- Division of Nephrology, Boston Children's Hospital, Boston, MA, USA
- Kidney Disease Initiative & Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomoko Horinouchi
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Seulgi Jung
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Songpa-gu, Seoul, Korea
| | - Manuela Colucci
- Renal Diseases Research Unit, Genetics and Rare Diseases Research Division, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Dina F Ahram
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Adele Mitrotti
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Aditi Sinha
- Department of Pediatrics, AIIMS, New Delhi, India
| | - Nynke Teeninga
- Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Gina Jin
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Shirlee Shril
- Department of Medicine, Boston Children's Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Gianluca Caridi
- Laboratory on Molecular Nephrology, IRCCS Instituto Giannina Gaslini, Genoa, Italy
| | - Monica Bodria
- Department of Nephrology and Renal Transplantation, IRCCS Instituto Giannina Gaslini, Genoa, Italy
| | - Tze Y Lim
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Rik Westland
- Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands
| | - Francesca Zanoni
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
- Division of Transplantation, Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA
| | - Maddalena Marasa
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Daniel Turudic
- Department of Pediatric Nephrology, Dialysis and Transplantation, Clinical Hospital Hospital Center Zagreb, University of Zagreb Medical School, Zagreb, Croatia
| | - Mario Giordano
- Division of Nephrology and Pediatric Dialysis, Bari Polyclinic Giovanni XXIII Children's Hospital, Bari, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Riccardo Magistroni
- Department of Nephrology, Dialysis and Transplant Unit, University Hospital of Modena, Modena, Italy
- Surgical, Medical and Dental Department of Morphological Sciences, Section of Nephrology, University of Modena and Reggio Emilia, Modena, Italy
| | - Isabella Pisani
- Unità Operativa Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
| | - Enrico Fiaccadori
- Unità Operativa Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
| | - Jana Reiterova
- Department of Nephrology, Medicine and General University Hospital, Charles University, Prague, Czech Republic
| | | | - William Morello
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milano, Italy
| | - Giovanni Montini
- Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milano, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Patricia L Weng
- Department of Pediatric Nephrology, UCLA Medical Center and UCLA Medical Center-Santa Monica, Los Angeles, CA, USA
| | - Francesco Scolari
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Division of Nephrology and Dialysis, University of Brescia and ASST Spedali Civili of Brescia, Brescia, Italy
| | - Marijan Saraga
- Department of Pediatrics, University of Split, Split, Croatia
| | - Velibor Tasic
- Department of Pediatric Nephrology, University Children's Hospital, Skopje, Macedonia
| | - Domenica Santoro
- Division of Nephrology and Dialysis Unit, University of Messina, Sicily, Italy
| | - Joanna A E van Wijk
- Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The Netherlands
| | - Danko Milošević
- Department of Pediatric Nephrology, Dialysis and Transplantation, Clinical Hospital Hospital Center Zagreb, University of Zagreb Medical School, Zagreb, Croatia
- Croatian Academy of Medical Sciences, Praska 2/III p.p. 27, 10000, Zagreb, Croatia
| | - Yosuke Kawai
- Genome Medical Science Project (Toyama), National Center for Global Health and Medicine (NCGM), Tokyo, Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Krzysztof Kiryluk
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Martin R Pollak
- Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Department of Pediatric, Division of Pediatric Nephrology, Columbia University Irving Medical Center New York-Presbyterian Morgan Stanley Children's Hospital in New York, New York, NY, USA
| | - Ali Gharavi
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Fangmin Lin
- Department of Pediatric, Division of Pediatric Nephrology, Columbia University Irving Medical Center New York-Presbyterian Morgan Stanley Children's Hospital in New York, New York, NY, USA
| | - Ana Cristina Simœs E Silva
- Department of Pediatrics, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Ruth J F Loos
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eimear E Kenny
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Genomic Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of General Internal Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Michiel F Schreuder
- Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Aleksandra Zurowska
- Department of Pediatrics, Nephrology and Hypertension, Medical University Gdansk, Gdansk, Poland
| | - Claire Dossier
- AP-HP, Pediatric Nephrology Department, Hôpital Robert-Debré, Paris, France
| | - Gema Ariceta
- Pediatric Nephrology, Hospital Universitari Vall d'Hebron, Universitat Autónoma de Barcelona, Barcelona, Spain
| | | | - Julien Hogan
- AP-HP, Pediatric Nephrology Department, Hôpital Robert-Debré, Paris, France
| | - Augustina Jankauskiene
- Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Friedhelm Hildebrandt
- Division of Nephrology, Boston Children's Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Larisa Prikhodina
- Research and Clinical Institute for Pediatrics, Pirogov Russian National Research Medical University, Taldomskava St, 2, Moscow, Russia
| | - Kyuyoung Song
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Songpa-gu, Seoul, Korea
| | - Arvind Bagga
- Department of Pediatrics, AIIMS, New Delhi, India
| | - Hae Cheong
- Department of Pediatrics, Hallym University Sacred Heart Hospital, 22, Gwanpyeong-ro 170 beon-gil, Dongan-gu, Anyang-si, Gyeonggi-do, 14068, Korea
| | - Gian Marco Ghiggeri
- Department of Nephrology and Renal Transplantation, IRCCS Instituto Giannina Gaslini, Genoa, Italy
| | - Prayong Vachvanichsanong
- Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Hat-Yai, Songkhla, 90110, Thailand
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Dongwon Lee
- Division of Nephrology, Boston Children's Hospital, Boston, MA, USA
- Kidney Disease Initiative & Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Marina Vivarelli
- Division of Nephrology, and Dialysis, Department of Pediatric Subspecialities, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Soumya Raychaudhuri
- Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
- Centre for Genetics and Genomics Versus Arthritis, University of Manchester, Manchester, UK
| | - Katsushi Tokunaga
- Genome Medical Science Project (Toyama), National Center for Global Health and Medicine (NCGM), Tokyo, Japan
- Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Simone Sanna-Cherchi
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Pierre Ronco
- Sorbonne Université, UPMC Paris 06, Institut National de la Santé et de la Recherde Médicale, Unité Mixte de Rechereche, S 1155, Paris, France
- Department of Nephrology, Centre Hospitalier du Mans, Le Mans, France
| | - Kazumoto Iijima
- Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan
- Department of Advanced Pediatric Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Matthew G Sampson
- Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.
- Kidney Disease Initiative & Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
- Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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16
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Liu S, Bush WS, Miskimen K, Gonzalez-Vicente A, Bailey JNC, Konidari I, McCauley JL, Sedor JR, O'Toole JF, Crawford DC. T-cell receptor diversity in minimal change disease in the NEPTUNE study. Pediatr Nephrol 2023; 38:1115-1126. [PMID: 35943576 PMCID: PMC10037226 DOI: 10.1007/s00467-022-05696-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 07/15/2022] [Accepted: 07/15/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Minimal change disease (MCD) is the major cause of childhood idiopathic nephrotic syndrome, which is characterized by massive proteinuria and debilitating edema. Proteinuria in MCD is typically rapidly reversible with corticosteroid therapy, but relapses are common, and children often have many adverse events from the repeated courses of immunosuppressive therapy. The pathobiology of MCD remains poorly understood. Prior clinical observations suggest that abnormal T-cell function may play a central role in MCD pathogenesis. Based on these observations, we hypothesized that T-cell responses to specific exposures or antigens lead to a clonal expansion of T-cell subsets, a restriction in the T-cell repertoire, and an elaboration of specific circulating factors that trigger disease onset and relapses. METHODS To test these hypotheses, we sequenced T-cell receptors in fourteen MCD, four focal segmental glomerulosclerosis (FSGS), and four membranous nephropathy (MN) patients with clinical data and blood samples drawn during active disease and during remission collected by the Nephrotic Syndrome Study Network (NEPTUNE). We calculated several T-cell receptor diversity metrics to assess possible differences between active disease and remission states in paired samples. RESULTS Median productive clonality did not differ between MCD active disease (0.0083; range: 0.0042, 0.0397) and remission (0.0088; range: 0.0038, 0.0369). We did not identify dominant clonotypes in MCD active disease, and few clonotypes were shared with FSGS and MN patients. CONCLUSIONS While these data do not support an obvious role of the adaptive immune system T-cells in MCD pathogenesis, further study is warranted given the limited sample size. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Shiying Liu
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
- Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
| | - William S Bush
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
- Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Kristy Miskimen
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
- Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA
| | - Agustin Gonzalez-Vicente
- Glickman Urological and Kidney Disease and Lerner Research Institutes, Cleveland Clinic, Cleveland, OH, USA
| | - Jessica N Cooke Bailey
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
- Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA
| | - Ioanna Konidari
- John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Jacob L McCauley
- John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - John R Sedor
- Glickman Urological and Kidney Disease and Lerner Research Institutes, Cleveland Clinic, Cleveland, OH, USA
| | - John F O'Toole
- Glickman Urological and Kidney Disease and Lerner Research Institutes, Cleveland Clinic, Cleveland, OH, USA
| | - Dana C Crawford
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
- Cleveland Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA.
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
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17
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Li D, Liu L, Murea M, Freedman BI, Ma L. Bioinformatics Analysis Reveals a Shared Pathway for Common Forms of Adult Nephrotic Syndrome. KIDNEY360 2023; 4:e515-e524. [PMID: 36763793 PMCID: PMC10278839 DOI: 10.34067/kid.0000000000000074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 01/20/2023] [Indexed: 02/12/2023]
Abstract
Key Points Dysregulation of the focal adhesion pathway is present in the three most common forms of glomerular disease, that is, Focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease. Zyxin is seen to be upregulated in the glomerular compartment of patients with the three most common forms of glomerular disease. Background Focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease are common causes of nephrotic syndrome. Although triggers for these diseases differ, disease progression may share common molecular mechanisms. The aim of this study was to investigate the presence of molecular pathways that are dysregulated across these glomerular diseases. Methods The gene expression dataset GSE200828 from the Nephrotic Syndrome Study Network study was obtained from the Gene Expression Omnibus database. R and Python packages, Cytoscape software, and online tools (DAVID and STRING) were used to identify core genes and topologically relevant nodes and molecular pathways. Single-cell RNA sequencing analysis was applied to identify the expression patterns of core genes across kidney cell types in glomerular compartments. Results A total of 1087 differentially expressed genes were identified, including 691 upregulated genes and 396 downregulated genes, which are common in all three forms of nephrotic syndrome compared with kidney donor controls (FDR P <0.01). A multiapproach bioinformatics analysis narrowed down to 28 similarly dysregulated genes across the three proteinuric glomerulopathies. The most topologically relevant nodes belonged to the adherens junction, focal adhesion, and cytoskeleton pathways, where zyxin covers all of those gene ontology terms. Conclusions We report that dysregulation of cell adhesion complexes was present in the three most common forms of glomerular disease. Zyxin could be a biomarker in all three common forms of nephrotic syndrome. If further functional studies confirm its role in their development, zyxin could be a potential therapeutic target.
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Affiliation(s)
- DengFeng Li
- Informatics and Analytics, The University of North Carolina at Greensboro, Greensboro, North Carolina
| | - Liang Liu
- Bioinformatics Shared Resource, Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Mariana Murea
- Department of Internal Medicine—Nephrology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Barry I. Freedman
- Department of Internal Medicine—Nephrology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
| | - Lijun Ma
- Department of Internal Medicine—Nephrology, Wake Forest University School of Medicine, Winston-Salem, North Carolina
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18
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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: 1] [Impact Index Per Article: 0.5] [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.
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19
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Batal I, Khairallah P, Weins A, Andeen NK, Stokes MB. The role of HLA antigens in recurrent primary focal segmental glomerulosclerosis. Front Immunol 2023; 14:1124249. [PMID: 36911713 PMCID: PMC9995699 DOI: 10.3389/fimmu.2023.1124249] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 02/06/2023] [Indexed: 02/25/2023] Open
Abstract
Primary focal segmental glomerulosclerosis (FSGS), typically characterized by diffuse podocyte foot process effacement and nephrotic syndrome (diffuse podocytopathy), is generally attributed to a circulating permeability factor. Primary FSGS can recur after transplantation where it manifests as diffuse foot process effacement in the early stages, with subsequent evolution of segmental sclerotic lesions. Previous published literature has been limited by the lack of stringent selection criteria to define primary FSGS. Although immunogenetic factors play an important role in many glomerular diseases, their role in recurrent primary FSGS post-transplantation has not been systematically investigated. To address this, we retrospectively studied a multicenter cohort of 74 kidney allograft recipients with end stage kidney disease due to primary FSGS, confirmed by clinical and histologic parameters. After adjusting for race/ethnicity, there was a numeric higher frequency of HLA-A30 antigen in primary FSGS (19%) compared to each of 22,490 healthy controls (7%, adjusted OR=2.0, P=0.04) and 296 deceased kidney donors (10%, OR=2.1, P=0.03). Within the group of transplant patients with end stage kidney disease due to primary FSGS, donor HLA-A30 was associated with recurrent disease (OR=9.1, P=0.02). Multivariable time-to-event analyses revealed that recipients who self-identified as Black people had lower risk of recurrent disease, probably reflecting enrichment of these recipients with APOL1 high-risk genotypes. These findings suggest a role for recipient and donor immunogenetic makeup in recurrent primary FSGS post-transplantation. Further larger studies in well-defined cohorts of primary FSGS that include high-resolution HLA typing and genome-wide association are necessary to refine these hereditary signals.
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Affiliation(s)
- Ibrahim Batal
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, United States
| | - Pascale Khairallah
- Medicine, Division of Nephrology, Columbia University Irving Medical Center, New York, NY, United States
| | - Astrid Weins
- Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Nicole K Andeen
- Pathology, Oregon Health & Science University, Portland, OR, United States
| | - Michael B Stokes
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, United States
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20
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Madison J, Wilhelm K, Meehan DT, Delimont D, Samuelson G, Cosgrove D. Glomerular basement membrane deposition of collagen α1(III) in Alport glomeruli by mesangial filopodia injures podocytes via aberrant signaling through DDR1 and integrin α2β1. J Pathol 2022; 258:26-37. [PMID: 35607980 PMCID: PMC9378723 DOI: 10.1002/path.5969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/29/2022] [Accepted: 05/20/2022] [Indexed: 11/20/2022]
Abstract
In Alport mice, activation of the endothelin A receptor (ETA R) in mesangial cells results in sub-endothelial invasion of glomerular capillaries by mesangial filopodia. Filopodia deposit mesangial matrix in the glomerular basement membrane (GBM), including laminin 211 which activates NF-κB, resulting in induction of inflammatory cytokines. Herein we show that collagen α1(III) is also deposited in the GBM. Collagen α1(III) localized to the mesangium in wild-type mice and was found in both the mesangium and the GBM in Alport mice. We show that collagen α1(III) activates discoidin domain receptor family, member 1 (DDR1) receptors both in vitro and in vivo. To elucidate whether collagen α1(III) might cause podocyte injury, cultured murine Alport podocytes were overlaid with recombinant collagen α1(III), or not, for 24 h and RNA was analyzed by RNA sequencing (RNA-seq). These same cells were subjected to siRNA knockdown for integrin α2 or DDR1 and the RNA was analyzed by RNA-seq. Results were validated in vivo using RNA-seq from RNA isolated from wild-type and Alport mouse glomeruli. Numerous genes associated with podocyte injury were up- or down-regulated in both Alport glomeruli and cultured podocytes treated with collagen α1(III), 18 of which have been associated previously with podocyte injury or glomerulonephritis. The data indicate α2β1 integrin/DDR1 co-receptor signaling as the dominant regulatory mechanism. This may explain earlier studies where deletion of either DDR1 or α2β1 integrin in Alport mice ameliorates renal pathology. © 2022 Boys Town National Research Hospital. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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21
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Lausecker F, Koehler S, Fresquet M, Naylor RW, Tian P, Wanner N, Braun F, Butt L, Huber TB, Lennon R. Integrating basic science with translational research: the 13th International Podocyte Conference 2021. Kidney Int 2022; 102:708-719. [PMID: 35964799 PMCID: PMC9386279 DOI: 10.1016/j.kint.2022.07.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/20/2022] [Accepted: 07/26/2022] [Indexed: 11/30/2022]
Abstract
The 13th International Podocyte Conference was held in Manchester, UK, and online from July 28 to 30, 2021. Originally planned for 2020, this biannual meeting was postponed by a year because of the coronavirus disease 2019 (COVID-19) pandemic and proceeded as an innovative hybrid meeting. In addition to in-person attendance, online registration was offered, and this attracted 490 conference registrations in total. As a Podocyte Conference first, a day for early-career researchers was introduced. This premeeting included talks from graduate students and postdoctoral researchers. It gave early career researchers the opportunity to ask a panel, comprising academic leaders and journal editors, about career pathways and the future for podocyte research. The main meeting over 3 days included a keynote talk and 4 focused sessions each day incorporating invited talks, followed by selected abstract presentations, and an open panel discussion. The conference concluded with a Patient Day, which brought together patients, clinicians, researchers, and industry representatives. The Patient Day was an interactive and diverse day. As well as updates on improving diagnosis and potential new therapies, the Patient Day included a PodoArt competition, exercise and cooking classes with practical nutrition advice, and inspirational stories from patients and family members. This review summarizes the exciting science presented during the 13th International Podocyte Conference and demonstrates the resilience of researchers during a global pandemic.
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Affiliation(s)
- Franziska Lausecker
- Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Sybille Koehler
- Biomedical Sciences, University of Edinburgh, Edinburgh, UK; III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maryline Fresquet
- Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Richard W Naylor
- Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Pinyuan Tian
- Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Nicola Wanner
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Fabian Braun
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Linus Butt
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Tobias B Huber
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Rachel Lennon
- Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Department of Paediatric Nephrology, Royal Manchester Children's Hospital, Manchester University Hospitals National Health Service (NHS) Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
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22
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Genetics in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2022; 101:1126-1141. [PMID: 35460632 PMCID: PMC9922534 DOI: 10.1016/j.kint.2022.03.019] [Citation(s) in RCA: 69] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/16/2022] [Accepted: 03/29/2022] [Indexed: 01/19/2023]
Abstract
Numerous genes for monogenic kidney diseases with classical patterns of inheritance, as well as genes for complex kidney diseases that manifest in combination with environmental factors, have been discovered. Genetic findings are increasingly used to inform clinical management of nephropathies, and have led to improved diagnostics, disease surveillance, choice of therapy, and family counseling. All of these steps rely on accurate interpretation of genetic data, which can be outpaced by current rates of data collection. In March of 2021, Kidney Diseases: Improving Global Outcomes (KDIGO) held a Controversies Conference on "Genetics in Chronic Kidney Disease (CKD)" to review the current state of understanding of monogenic and complex (polygenic) kidney diseases, processes for applying genetic findings in clinical medicine, and use of genomics for defining and stratifying CKD. Given the important contribution of genetic variants to CKD, practitioners with CKD patients are advised to "think genetic," which specifically involves obtaining a family history, collecting detailed information on age of CKD onset, performing clinical examination for extrarenal symptoms, and considering genetic testing. To improve the use of genetics in nephrology, meeting participants advised developing an advanced training or subspecialty track for nephrologists, crafting guidelines for testing and treatment, and educating patients, students, and practitioners. Key areas of future research, including clinical interpretation of genome variation, electronic phenotyping, global representation, kidney-specific molecular data, polygenic scores, translational epidemiology, and open data resources, were also identified.
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23
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Identification of Nephrin gene variants in Indian children associated with Steroid sensitive and Steroid resistant nephrotic syndrome. Meta Gene 2022. [DOI: 10.1016/j.mgene.2021.101004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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24
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Colucci M, Oniszczuk J, Vivarelli M, Audard V. B-Cell Dysregulation in Idiopathic Nephrotic Syndrome: What We Know and What We Need to Discover. Front Immunol 2022; 13:823204. [PMID: 35140723 PMCID: PMC8819007 DOI: 10.3389/fimmu.2022.823204] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 01/04/2022] [Indexed: 11/18/2022] Open
Abstract
The therapeutic efficacy of B-cell depletion by anti-CD20 treatment in pediatric and, more recently, in adult idiopathic nephrotic syndrome patients suggests a key role of B cells in the pathogenesis of the disease. However, their exact role is still unclear. B cells are able to secrete a large variety of antibodies that can protect against infections. However, B-cell dysregulation is well-established in a variety of autoimmune diseases. In parallel with their ability to produce antibodies, pathogenic B cells display altered effector functions by expressing activating surface molecules, which can strongly modify the immune homeostasis, or by producing specific cytokines, which can directly affect either podocyte structure and functions or modulate T-cell homeostasis. Herein, we report the most relevant clinical and experimental evidences of a pathogenic role of B cells in idiopathic nephrotic syndrome. We further highlight similarities and differences between children and adults affected by non-genetic forms of the disease and discuss what needs to be investigated in order to define the exact mechanisms underlying the pathogenic role of B cells and to identify more tailored therapeutic approaches.
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Affiliation(s)
- Manuela Colucci
- Renal Diseases Research Unit, Genetics and Rare Diseases Research Area, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
- *Correspondence: Manuela Colucci,
| | - Julie Oniszczuk
- Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri-Mondor, Service de Néphrologie et Transplantation, Centre de Référence Maladie Rare “Syndrome Néphrotique Idiopathique”, Fédération Hospitalo-Universitaire, Innovative Therapy for Immune Disorders, Créteil, France
- Univ Paris Est Créteil, Institut National de la Santé et de la Recherche Médicale (INSERM) U955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil, France
| | - Marina Vivarelli
- Division of Nephrology, Department of Pediatric Subspecialties, Bambino Gesù Children’s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome, Italy
| | - Vincent Audard
- Assistance Publique des Hôpitaux de Paris, Hôpitaux Universitaires Henri-Mondor, Service de Néphrologie et Transplantation, Centre de Référence Maladie Rare “Syndrome Néphrotique Idiopathique”, Fédération Hospitalo-Universitaire, Innovative Therapy for Immune Disorders, Créteil, France
- Univ Paris Est Créteil, Institut National de la Santé et de la Recherche Médicale (INSERM) U955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil, France
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25
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Purohit S, Piani F, Ordoñez FA, de Lucas-Collantes C, Bauer C, Cara-Fuentes G. Molecular Mechanisms of Proteinuria in Minimal Change Disease. Front Med (Lausanne) 2022; 8:761600. [PMID: 35004732 PMCID: PMC8733331 DOI: 10.3389/fmed.2021.761600] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/15/2021] [Indexed: 11/13/2022] Open
Abstract
Minimal change disease (MCD) is the most common type of idiopathic nephrotic syndrome in childhood and represents about 15% cases in adults. It is characterized by massive proteinuria, edema, hypoalbuminemia, and podocyte foot process effacement on electron microscopy. Clinical and experimental studies have shown an association between MCD and immune dysregulation. Given the lack of inflammatory changes or immunocomplex deposits in the kidney tissue, MCD has been traditionally thought to be mediated by an unknown circulating factor(s), probably released by T cells that directly target podocytes leading to podocyte ultrastructural changes and proteinuria. Not surprisingly, research efforts have focused on the role of T cells and podocytes in the disease process. Nevertheless, the pathogenesis of the disease remains a mystery. More recently, B cells have been postulated as an important player in the disease either by activating T cells or by releasing circulating autoantibodies against podocyte targets. There are also few reports of endothelial injury in MCD, but whether glomerular endothelial cells play a role in the disease remains unexplored. Genome-wide association studies are providing insights into the genetic susceptibility to develop the disease and found a link between MCD and certain human haplotype antigen variants. Altogether, these findings emphasize the complex interplay between the immune system, glomerular cells, and the genome, raising the possibility of distinct underlying triggers and/or mechanisms of proteinuria among patients with MCD. The heterogeneity of the disease and the lack of good animal models of MCD remain major obstacles in the understanding of MCD. In this study, we will review the most relevant candidate mediators and mechanisms of proteinuria involved in MCD and the current models of MCD-like injury.
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Affiliation(s)
- Shrey Purohit
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Pediatrics, Section of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, United States
| | - Federica Piani
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Medicine and Surgery Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Flor A Ordoñez
- Division of Pediatric Nephrology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | | | - Colin Bauer
- Department of Pediatrics, Section of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, United States
| | - Gabriel Cara-Fuentes
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Pediatrics, Section of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, United States
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26
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Zanoni F, Khairallah P, Kiryluk K, Batal I. Glomerular Diseases of the Kidney Allograft: Toward a Precision Medicine Approach. Semin Nephrol 2022; 42:29-43. [PMID: 35618394 PMCID: PMC9139085 DOI: 10.1016/j.semnephrol.2022.01.005] [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: 01/03/2023]
Abstract
The continual development of potent immunosuppressive regimens has led to a decreased incidence of acute rejection and improvement of short-term kidney allograft survival. In contrast to acute rejection, glomerular diseases of the kidney allograft are being encountered more frequently and are emerging as leading causes of late kidney allograft failure. Although data on the pathogeneses of glomerular diseases in the kidney allograft are sparse, cumulative evidence suggests that post-transplant glomerular diseases may be the result of inherited predispositions and immunologic triggers. Although studying immunologic signals and performing genome-wide association studies are ideal approaches to tackle glomerular diseases in the kidney allograft, such studies are challenging because of the lack of adequately powered cohorts. In this review, we focus on the most commonly encountered recurrent and de novo glomerular diseases in the kidney allograft. We address the important advances made in understanding the immunopathology and genetic susceptibility of glomerular diseases in the native kidney and how to benefit from such knowledge to further our knowledge of post-transplant glomerular diseases. Defining genomic and immune predictors for glomerular diseases in the kidney allograft would support novel donor-recipient matching strategies and development of targeted therapies to ultimately improve long-term kidney allograft survival.
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Affiliation(s)
- Francesca Zanoni
- Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY, USA
| | | | - Krzysztof Kiryluk
- Medicine, Nephrology, Columbia University Irving Medical Center, New York, NY, USA
| | - Ibrahim Batal
- Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA,Corresponding Author: Ibrahim Batal MD, Department of Pathology and Cell Biology, Renal Division, Columbia University Irving Medical Center, 630 W 168th street, VC14-238, New York, NY 10032, Phone: 212-305-9669, Fax: 212-342-5380,
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27
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Horinouchi T, Nozu K, Iijima K. An updated view of the pathogenesis of steroid-sensitive nephrotic syndrome. Pediatr Nephrol 2022; 37:1957-1965. [PMID: 35006356 PMCID: PMC9307535 DOI: 10.1007/s00467-021-05401-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 11/01/2021] [Accepted: 11/24/2021] [Indexed: 11/28/2022]
Abstract
Idiopathic nephrotic syndrome is the most common childhood glomerular disease. Most forms of this syndrome respond to corticosteroids at standard doses and are, therefore, defined as steroid-sensitive nephrotic syndrome (SSNS). Immunological mechanisms and subsequent podocyte disorders play a pivotal role in SSNS and have been studied for years; however, the precise pathogenesis remains unclear. With recent advances in genetic techniques, an exhaustive hypothesis-free approach called a genome-wide association study (GWAS) has been conducted in various populations. GWASs in pediatric SSNS peaked in the human leukocyte antigen class II region in various populations. Additionally, an association of immune-related CALHM6/FAM26F, PARM1, BTNL2, and TNFSF15 genes, as well as NPHS1, which encodes nephrin expressed in podocytes, has been identified as a locus that achieves genome-wide significance in pediatric SSNS. However, the specific mechanism of SSNS development requires elucidation. This review describes an updated view of SSNS pathogenesis from immunological and genetic aspects, including interactions with infections or allergies, production of circulating factors, and an autoantibody hypothesis.
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Affiliation(s)
- Tomoko Horinouchi
- grid.31432.370000 0001 1092 3077Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kandai Nozu
- grid.31432.370000 0001 1092 3077Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazumoto Iijima
- Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan. .,Department of Advanced Pediatric Medicine, Kobe University Graduate School of Medicine, Minatojimaminami-machi 1-6-7, Chuo-ku, Kobe, 650-0047, Japan.
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28
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Rong L, Chen L, Rao J, Shen Q, Li G, Liu J, Mao J, Feng C, Wang X, Wang S, Kuang X, Huang W, Ma Q, Liu X, Ling C, Fu R, Gao X, Ding G, Yang H, Han M, Huang Z, Li Q, Zhang Q, Lin Y, Jiang X, Xu H. Genetic Variations and Clinical Features of NPHS1-Related Nephrotic Syndrome in Chinese Children: A Multicenter, Retrospective Study. Front Med (Lausanne) 2021; 8:771227. [PMID: 34859019 PMCID: PMC8632042 DOI: 10.3389/fmed.2021.771227] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/05/2021] [Indexed: 11/16/2022] Open
Abstract
Introduction: Few studies have addressed the genetic spectrum of NPHS1 variants in Chinese children with nephrotic syndrome. In this multicenter study, the clinical manifestations and features of NPHS1 variants in Chinese children with nephrotic syndrome were researched. Method: Genotypical and phenotypical data from 30 children affected by NPHS1 variants were collected from a multicenter registration system in China and analyzed retrospectively. Results: The patients were divided into two groups: congenital nephrotic syndrome (CNS [n = 24]) and non-CNS (early onset nephrotic syndrome [n = 6]). Renal biopsy was performed on four patients in the non-CNS group, revealing minimal change disease in three and focal segmental glomerulosclerosis in one. A total of 61 NPHS1 variants were detected, involving 25 novel variants. The "recurrent variants" included c.928G>A(p.Asp310Asn) in eight patients with CNS, followed by c.616C>A(p.Pro206Thr) in four, and c.2207T>C (p.Val736Ala) in three. Steroid treatment was applied in 29.2% (7/24)of the patients in the CNS group and 50% (3/6) of the patients in the non-CNS group. One patient in each group experienced complete remission but relapsed subsequently. Immunosuppressants were administered to three patients in the non-CNS group, eliciting an effective response. In the CNS group, three patients underwent renal transplantation and six died mainly from infection. Conclusion: Variants of NPHS1 cause CNS and early childhood-onset nephrotic syndrome. NPHS1 variants in Chinese individuals with nephrotic syndrome (NS) were mainly compound heterozygous variants, and c.928G>A(p.Asp310Asn) in exon 8 may act as a recurrent variant in the Chinese population, followed by c.616C>A(p.Pro206Thr) in exon 6. Steroids and immunosuppressants may be effective in selected patients.
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Affiliation(s)
- Liping Rong
- Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lizhi Chen
- Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jia Rao
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
| | - Qian Shen
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
| | - Guomin Li
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
| | - Jialu Liu
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
| | - Jianhua Mao
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chunyue Feng
- Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaowen Wang
- Department of Nephrology and Rheumatology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Si Wang
- Department of Nephrology and Rheumatology, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Xinyu Kuang
- Department of Nephrology and Rheumatology, Children's Hospital of Shanghai Jiaotong University, Shanghai, China
| | - Wenyan Huang
- Department of Nephrology and Rheumatology, Children's Hospital of Shanghai Jiaotong University, Shanghai, China
| | - Qingshan Ma
- Department of Pediatric Nephrology, First Hospital, Jilin University, Changchun, China
| | - Xiaorong Liu
- Department of Nephrology, Bejing Children's Hospital Affiliated to Capital University of Medical Science, Beijing, China
| | - Chen Ling
- Department of Nephrology, Bejing Children's Hospital Affiliated to Capital University of Medical Science, Beijing, China
| | - Rong Fu
- Department of Pediatrics, Puyang Oilfield General Hospital, Puyang, China
| | - Xiaojie Gao
- Department of Nephrology, Shenzhen Children's Hospital, Shenzhen, China
| | - Guixia Ding
- Department of Nephrology, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Huandan Yang
- Department of Nephrology, Xuzhou Children's Hospital, Xuzhou, China
| | - Mei Han
- Department of Nephrology, Children's Hospital of Dalian Medical University, Dalian, China
| | - Zhimin Huang
- Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Qian Li
- Department of Pediatric Nephrology, Rheumatism and Immunology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong, China
| | - Qiuye Zhang
- Department of Pediatrics, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yi Lin
- Department of Pediatrics, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaoyun Jiang
- Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hong Xu
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
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Tamura H. Trends in pediatric nephrotic syndrome. World J Nephrol 2021; 10:88-100. [PMID: 34631479 PMCID: PMC8477269 DOI: 10.5527/wjn.v10.i5.88] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/15/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Nephrotic syndrome (NS) is relatively common in children, with most of its histological types being minimal changed disease. Its etiology has long been attributed to lymphocyte (especially T-cell) dysfunction, while T-cell-mediated vascular hyperpermeability increases protein permeability in glomerular capillaries, leading to proteinuria and hypoproteinemia. Based on this etiology, steroids and immunosuppressive drugs that are effective against this disease have also been considered to correct T-cell dysfunction. However, in recent years, this has been questioned. The primary cause of NS has been considered damage to glomerular epithelial cells and podocyte-related proteins. Therefore, we first describe the changes in expression of molecules involved in NS etiology, and then describe the mechanism by which abnormal expression of these molecules induces proteinuria. Finally, we consider the mechanism by which infection causes the recurrence of NS.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
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30
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Tsuji S, Kaneko K. The long and winding road to the etiology of idiopathic nephrotic syndrome in children: Focusing on abnormalities in the gut microbiota. Pediatr Int 2021; 63:1011-1019. [PMID: 33657643 DOI: 10.1111/ped.14679] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 11/28/2022]
Abstract
Childhood nephrotic syndrome is idiopathic in 90% of cases. Despite its relatively high prevalence (30-35 per 100 000 individuals under 15 years old), the etiology of the disease remains elusive. It has become clear that oxidants are elevated, and antioxidants are decreased, at onset of idiopathic nephrotic syndrome (INS). It was suggested that overexpression of podocyte CD80 induced by abnormalities of Tregs was involved in the pathogenesis of INS. Subsequently, it became clear that quantitative or qualitative reduction of Tregs has a profound impact on the development of INS. To address why Tregs are decreased at onset of INS, it was hypothesized that a decrease in Tregs may be associated with dysbiosis. Given the critical role of butyrate-producing bacteria in the differentiation of Tregs, the gut microbiota was analyzed with a particular focus on the abundance of butyrate-producing bacteria, and it was found that pediatric patients with INS had low levels of butyrate in their stool and a low percentage of butyrate-producing bacteria. Interestingly, it was recently reported that gut dysbiosis increases oxidative stress in the intestinal tract. Taken together, we currently hypothesize that gut dysbiosis is associated with a predisposition to INS because of immunological abnormalities characterized by abnormal Tregs with increased oxidative stress.
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Affiliation(s)
- Shoji Tsuji
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
| | - Kazunari Kaneko
- Department of Pediatrics, Kansai Medical University, Osaka, Japan
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31
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Novel insights in the genetics of steroid-sensitive nephrotic syndrome in childhood. Pediatr Nephrol 2021; 36:2165-2175. [PMID: 33084934 DOI: 10.1007/s00467-020-04780-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/10/2020] [Accepted: 09/14/2020] [Indexed: 10/23/2022]
Abstract
Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of nephrotic syndrome in childhood and there is growing evidence that genetics play a role in the susceptibility for the disease. Familial clustering has been observed and has led to several studies on familial SSNS trying to identify a monogenic cause of the disease. Until now, however, none of these have provided convincing evidence for Mendelian inheritance. This and the phenotypic variability within SSNS suggest a complex inheritance pattern, where multiple variants and interactions between those and the environment play roles in disease development. Genome-wide association studies (GWASs) have been used to investigate this complex disease. We herein highlight new insights in the genetics of the disease provided by GWAS and identify how these insights fit into our understanding of the pathogenesis of SSNS.
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32
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Gbadegesin RA, Hernandez LPH, Brophy PD. Case Report: Novel Dietary Supplementation Associated With Kidney Recovery and Reduction in Proteinuria in a Dialysis Dependent Patient Secondary to Steroid Resistant Minimal Change Disease. Front Pediatr 2021; 9:614948. [PMID: 34017803 PMCID: PMC8129002 DOI: 10.3389/fped.2021.614948] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 03/26/2021] [Indexed: 01/13/2023] Open
Abstract
Minimal change disease (MCD) is the most common cause of nephrotic syndrome worldwide. For decades, the foundation of the treatment has been corticosteroids. However, relapse rate is high and up to 40% of patients develop frequent relapsing/steroid dependent course and one third become steroid resistant. This requires treatment with repeated courses of corticosteroids, and second and third line immunomodulators increasing the incidence of drug related adverse effects. More recently, there have been reports of a very small subset of Nephrotic Syndrome (NS) patients who are initially steroid sensitive and later become secondarily steroid resistant. The disease course in this small subset is often protracted leading ultimately to end stage kidney disease requiring dialysis or kidney transplantation. Unfortunately, patients with this disease course do not do well post transplantation because 80% of them will develop disease recurrence that will ultimately lead to graft failure. Few approaches have been tried over many years to reduce the frequency of relapses, and steroid dependence and there is absolutely no therapeutic intervention for patients who develop secondary steroid resistance. Nonetheless, their therapeutic index is low, evidencing the need of a safer complementary treatment. Several hypotheses, including an oxidative stress-mediated mechanism, and immune dysregulation have been proposed to date to explain the underlying mechanism of Minimal Change Disease (MCD) but its specific etiology remains elusive. Here, we report a case of a 54-year-old man with steroid and cyclosporine resistant MCD. The patient rapidly progressed to end stage kidney disease requiring initiation of chronic dialysis. Intradialytic parenteral nutrition (IDPN), albumin infusion along with a proprietary dietary supplement, as part of the supportive therapy, led to kidney function recovery and complete remission of MCD without relapses.
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Affiliation(s)
- Rasheed A Gbadegesin
- Division of Nephrology, Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States
| | | | - Patrick D Brophy
- University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
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