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Gong XJ, Huang J, Shu Y, Wang M, Ji J, Yang L, Zhao MH, Cui Z. Complement C5a and C5a receptor 1 mediates glomerular damage in focal segmental glomerulosclerosis. Clin Immunol 2025; 273:110459. [PMID: 39984108 DOI: 10.1016/j.clim.2025.110459] [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: 10/27/2024] [Revised: 02/15/2025] [Accepted: 02/18/2025] [Indexed: 02/23/2025]
Abstract
BACKGROUND Clinical data and animal models have provided compelling evidence supporting the pathogenic role of complement activation in the progression of focal segmental glomerulosclerosis (FSGS). However, the mechanisms underlying complement-induced podocyte injury and parietal epithelial cell (PEC) activation are not well understood. METHODS We evaluated glomerular C5aR1 (CD88) expression in FSGS patients and tested the effects of the C5aR1 antagonist (PMX205) in Adriamycin nephropathy mice. The effects on PECs and podocytes were evaluated following exposure to recombinant C5a or FSGS plasma, with or without the C5aR1 antagonist. RESULTS C5aR1 was overexpressed on PECs and podocytes in FSGS patients, with levels positively correlated with serum creatinine, the percentage of segmental glomerulosclerosis, and the prognosis of refractory nephrotic syndrome. In Adriamycin nephropathy mice, the C5aR1 antagonist significantly attenuated proteinuria, blood urea nitrogen levels, and the percentage of segmental and global glomerulosclerosis. It also alleviated PEC activation and proliferation, and mitigated podocyte loss. Moreover, glomerular IgM deposits were reduced, followed by decreased deposits of C3d and C5b-9. In vitro, PECs exposed to recombinant C5a exhibited upregulated expression of CD44 and Notch1, along with increased secretion of COL4A2. Podocytes exposed to FSGS plasma showed impaired cell viability and downregulation of synaptopodin, effects that were reversed by the C5aR1 antagonist. CONCLUSIONS These findings highlight the pathogenic role of the complement system in the development of FSGS through the C5a-C5aR1 axis on podocytes and PECs. The C5aR1 antagonist represents a promising therapeutic intervention for FSGS patients.
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Affiliation(s)
- Xiao-Jie Gong
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Jing Huang
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Yue Shu
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Miao Wang
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Jing Ji
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China; Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Li Yang
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Ming-Hui Zhao
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhao Cui
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China.
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Pilco-Terán M, Shabaka A, Furlano M, Tato Ribera A, Galán Carrillo I, Gutiérrez E, Torra R, Fernández-Juárez G. Indications for genetic testing in adults with focal segmental glomerulosclerosis. Nefrologia 2025; 45:135-149. [PMID: 39952830 DOI: 10.1016/j.nefroe.2025.02.001] [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: 06/30/2024] [Accepted: 09/23/2024] [Indexed: 02/17/2025] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a histological pattern of injury that derives from various pathological processes that affect podocytes, resulting in loss of selectivity of the glomerular filtration membrane, proteinuria and the development of renal failure that progresses to end-stage kidney disease in a significant number of patients. The classification proposed by the 2021 KDIGO guidelines divides FSGS into four categories: primary, secondary, genetic, and FSGS of undetermined cause, thus facilitating its diagnosis and management. Genetic causes of FSGS present significant clinical variability, complicating their identification. Genetic testing is crucial to identify FSGS of genetic cause. The prevalence of genetic FSGS is significant in children and considerable in adults, highlighting the importance of early diagnosis to avoid unnecessary treatments and facilitate genetic counselling. Massive sequencing techniques have revolutionized genetic diagnosis, allowing the identification of more than 60 genes responsible for podocyte damage. This document proposes clinical recommendations for carrying out genetic studies in adults with FSGS, highlighting the need for a correct classification for adequate therapeutic planning and improvement of results in clinical trials.
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Affiliation(s)
- Melissa Pilco-Terán
- Unidad de enfermedades renales hereditarias, Servicio de Nefrología, Fundació Puigvert, Instituto de investigación biomédica Hospital de Sant Pau, Universidad Autónoma de Barcelona, escuela de Medicina, Barcelona, Spain
| | - Amir Shabaka
- Servicio de Nefrología, Hospital Universitario La Paz, Madrid, Spain
| | - Mónica Furlano
- Unidad de enfermedades renales hereditarias, Servicio de Nefrología, Fundació Puigvert, Instituto de investigación biomédica Hospital de Sant Pau, Universidad Autónoma de Barcelona, escuela de Medicina, Barcelona, Spain
| | - Ana Tato Ribera
- Servicio de Nefrología, Hospital Universitario Fundación Alcorcón, Madrid, Spain
| | - Isabel Galán Carrillo
- Servicio de Nefrología, Hospital General Universitario Morales Meseguer, Murcia, Spain
| | - Eduardo Gutiérrez
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Roser Torra
- Unidad de enfermedades renales hereditarias, Servicio de Nefrología, Fundació Puigvert, Instituto de investigación biomédica Hospital de Sant Pau, Universidad Autónoma de Barcelona, escuela de Medicina, Barcelona, Spain
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Altintas MM, Agarwal S, Sudhini Y, Zhu K, Wei C, Reiser J. Pathogenesis of Focal Segmental Glomerulosclerosis and Related Disorders. ANNUAL REVIEW OF PATHOLOGY 2025; 20:329-353. [PMID: 39854184 PMCID: PMC11875227 DOI: 10.1146/annurev-pathol-051220-092001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2025]
Abstract
Focal segmental glomerulosclerosis (FSGS) is the morphologic manifestation of a spectrum of kidney diseases that primarily impact podocytes, cells that create the filtration barrier of the glomerulus. As its name implies, only parts of the kidney and glomeruli are affected, and only a portion of the affected glomerulus may be sclerosed. Although the diagnosis is based primarily on microscopic features, patient stratification relies on clinical data such as proteinuria and etiological criteria. FSGS affects both children and adults and has an elevated risk of progression to end-stage renal disease. The prevalence of FSGS is rising among various populations, and the efficacy of various therapies is limited. Therefore, understanding the pathophysiology of FSGS and developing targeted therapies to address the complex needs of FSGS patients are topics of great interest that are currently being studied across various clinical trials. We discuss the etiology of FSGS, describe the major contributing pathophysiological pathways, and outline emerging therapeutic strategies along with their pitfalls.
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Affiliation(s)
- Mehmet M Altintas
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | | | - Yashwanth Sudhini
- Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA
| | - Ke Zhu
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | - Changli Wei
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
| | - Jochen Reiser
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA;
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Jafry NH, Sarwar S, Waqar T, Mubarak M. Clinical course and outcome of adult patients with primary focal segmental glomerulosclerosis with kidney function loss on presentation. World J Nephrol 2024; 13:98932. [PMID: 39723357 PMCID: PMC11572652 DOI: 10.5527/wjn.v13.i4.98932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/28/2024] [Accepted: 10/21/2024] [Indexed: 11/07/2024] Open
Abstract
BACKGROUND Kidney function loss or renal insufficiency indicated by elevated creatinine levels and/or an estimated glomerular filtration rate (eGFR) < 60 mL/minute/1.73 m² at presentation in patients with primary focal segmental glomerulosclerosis (FSGS) is commonly seen as a poor prognostic marker for kidney survival. However, a pre>vious study from our center suggested this may be due to hemodynamic factors. AIM To observe the clinical and biochemical parameters, treatment response, kidney survival, and overall outcomes of adult patients with primary FSGS presenting with kidney function insufficiency. METHODS This retrospective observational study was conducted at the Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan, from January 1995 to December 2017. During this period, 401 biopsy-proven primary FSGS patients were identified, of which 98 (24.4%) presented with kidney function loss or renal insufficiency defined as eGFR < 60 mL/minute/1.73 m² at presentation and were studied in detail. RESULTS Among the 98 patients with renal function loss on presentation, the mean age was 30.9 years ± 13.6 years with a male-to-female ratio of 2.5:1. The mean serum creatinine level was 2.2 mg/dL ± 1.3 mg/dL and mean eGFR 37.1 mL/minute/1.73 m2 ± 12.8 mL/minute/1.73 m2. The mean 24-hour urinary protein excretion was 5.9 g/day ± 4.0 g/day, and the mean serum albumin was 2.1 g/dL ± 1.0 g/dL (median: 1.5 g/dL). The mean systolic blood pressure (BP) was 132.7 mmHg ± 19.8 mmHg, and the mean diastolic BP was 87.4 mmHg ± 12.7 mmHg. Steroid treatment was given to 81 (82.6%) of 98 patients for an average duration of 19.9 weeks ± 14.4 weeks, with a mean total steroid dose of 4.4 g ± 1.5 g. Treatment response showed that 20 (24.6%) patients achieved complete remission, 9 (11.1%) achieved partial remission, and 52 (64.1%) did not respond. The baseline eGFR was significantly lower in the non-responsive group (P = 0.006). The distribution of FSGS variants was also significantly different among steroid-responsive and non-responsive groups (P = 0.012). CONCLUSION Renal function loss in FSGS patients at presentation does not necessarily indicate irreversible kidney function loss and a significant number of patients respond to appropriate treatment of the underlying disease.
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Affiliation(s)
- Nazarul Hassan Jafry
- Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Sarfraz Sarwar
- Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Tajammul Waqar
- Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
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Goldschmidt D, Bensink ME, Zhou ZY, Shi S, Lin Y, Shi L. Epidemiology and burden of focal segmental glomerulosclerosis among United States Veterans: An analysis of Veteran's Affairs data. PLoS One 2024; 19:e0315302. [PMID: 39671357 PMCID: PMC11642916 DOI: 10.1371/journal.pone.0315302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 11/22/2024] [Indexed: 12/15/2024] Open
Abstract
INTRODUCTION Focal segmental glomerulosclerosis (FSGS) is a rare glomerular disease that can lead to reduced kidney function and kidney failure (KF). The objective of this study was to describe the epidemiology, characteristics, clinical outcomes, healthcare resource utilization, and costs associated with focal segmental glomerulosclerosis (FSGS) in United States (US) veterans. METHODS This retrospective cohort study included patients in the National Veterans Affairs Health Care Network with ≥2 FSGS-associated diagnostic codes that were 30-180 days apart (October 1999-February 2021). Annual FSGS incidence and prevalence per 1,000,000 US veterans were calculated. Patient and disease characteristics as of the index date (date of first FSGS diagnosis) and baseline (6-months pre-index) comorbidities were described. Kaplan-Meier analyses were used to assess overall survival and time from index to KF or death, dialysis, and kidney transplant. Post-index medication use, HRU, and direct healthcare costs were summarized. RESULTS The study included 2,515 veterans with FSGS who were followed for an average of 8.9 years. The mean age was 57.5 years, most patients were male (94.6%), and the most common comorbidity was hypertension (87.0%). The mean annual incidence and prevalence of FSGS during 2000-2020 were 19.6 and 164.7 per million veterans, respectively. Approximately half (51.5%) died during follow-up (median time: 11.6 years) and 76.9% had kidney failure (4.1 years). Overall, 43.3% underwent dialysis and 5.8% had a kidney transplant. During follow-up, statins and calcium channel blockers were commonly used (81.9% and 75.1%). During the first year post-index, 40% had an inpatient admission and 33% visited the emergency room; mean total healthcare cost per patient in the analysis was $36,543. CONCLUSIONS Among US veterans, FSGS is associated with considerable clinical and economic burdens. Better treatments for FSGS are needed to slow kidney disease progression, improve patient outcomes, and reduce the burden.
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Affiliation(s)
| | - Mark E. Bensink
- Travere Therapeutics, Inc., San Diego, California, United States of America
| | - Zheng-Yi Zhou
- Analysis Group, Boston, Massachusetts, United States of America
| | - Sherry Shi
- Analysis Group, Boston, Massachusetts, United States of America
| | - Yilu Lin
- Tulane University, New Orleans, Louisiana, United States of America
- Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana, United States of America
| | - Lizheng Shi
- Tulane University, New Orleans, Louisiana, United States of America
- Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana, United States of America
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Zhu Y, Chen B, Xu G. Efficacy and safety of nine immunosuppressive agents for primary focal segmental glomerulosclerosis in adults: a pairwise and network meta-analysis. Ren Fail 2024; 46:2438861. [PMID: 39663153 PMCID: PMC11636141 DOI: 10.1080/0886022x.2024.2438861] [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: 07/26/2024] [Revised: 11/30/2024] [Accepted: 12/02/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Immunosuppressants are widely used as the preferred treatment for primary focal segmental glomerulosclerosis (pFSGS). Nevertheless, controversies persist regarding the effectiveness and side effects of different immunosuppressive medications. METHODS From July 2023 until June 2024, we systematically searched PubMed, Cochrane Library, Web of Science, clinicalrials.gov, SinoMed, Chinese Biomedical, Chinese National Knowledge Infrastructure, Wanfang, and VIP information. Randomized controlled trials comparing different immunosuppressants were included in adult patients with pFSGS, with total remission (TR) and 24-h urine total protein (24-h UTP) as the main outcome measures. RESULTS We identified 20 RCTs comparing nine different immunosuppressants for the final analysis. Most immunosuppressants showed better therapeutic effects in TR compared to non-immunosuppressive therapies (NIT), with risk ratios (RRs) of 2.22 (95% CI 1.41-3.50) for cyclosporin, 2.10 (1.57-2.80) for leflunomide-combined steroids, 2.01 (1.24-3.27) for chlorambucil-combined steroids, 1.98 (1.17-3.33) for tacrolimus-combined steroids, 1.89 (1.36-2.63) for cyclosporin-combined steroids, 1.67 (1.28-2.18) for mycophenolate mofetil-combined steroids, and 1.47 (1.21-1.80) for steroids. Only mycophenolate mofetil-combined steroids (SMD -11, 95% CI -21 to -0.64) showed significant superiority in reducing 24-h UTP when compared with NIT. The subgroup analyses of steroids-resistant nephrotic syndrome (SRNS) patients showed that CSA + STE was significantly superior than the NIT group, with RR of 10.5 (95% CI 2.28-44.35). CONCLUSION Steroids remain the recommended initial treatment for pFSGS. For those patients with SRNS, CSA + STE might be the best choice for improving the rate of TR. LEF + STE and MMF + STE also appear to offer a steroid-saving alternative to high-dose glucocorticoids for patients.
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Affiliation(s)
- Yan Zhu
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, P. R. China
| | - Bo Chen
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, P. R. China
| | - Gaosi Xu
- Department of Nephrology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, P. R. China
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Wang L, Viswanathan S, Fischer E, Bose B. Focal segmental glomerulosclerosis (FSGS) in pregnancy: The case of a 27-year-old woman with nephrotic syndrome at 22 weeks of gestation. SAGE Open Med Case Rep 2024; 12:2050313X241300658. [PMID: 39544502 PMCID: PMC11561983 DOI: 10.1177/2050313x241300658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 10/28/2024] [Indexed: 11/17/2024] Open
Abstract
Nephrotic syndrome (NS) in pregnancy has been associated with poor fetal outcomes. Focal segmental glomerulosclerosis (FSGS) is one of the common causes of NS and can be primary or secondary. However, there are few case reports of FSGS diagnosed in the peripartum period and the approaches to management. We report the case of a 27-year-old gravida 2 para 1 Caucasian woman diagnosed with NS at 22 weeks of gestation. Her serum creatinine was 46 µmol/L (0.48 mg/dL), serum albumin 14 g/L (1.4 g/dL) and 24-h urinary protein 9.79 g/day with no haematuria. Serology was negative for lupus, phospholipase A2 receptor antibody, hepatitis and HIV. Paraprotein screening was also negative. The patient declined a renal biopsy. Differential diagnoses at this stage included minimal change disease and FSGS. Six weeks after commencing empirical treatment with high-dose oral prednisolone, there was no response; hence, tacrolimus was initiated. Due to concern for maternal and fetal well-being, the decision was made to deliver via Caesarean section at 31 weeks, given worsening proteinuria (23.18 g/24 h). A live male infant was delivered weighing 1625 g. Renal biopsy at 4 weeks post-partum was consistent with primary FSGS. This case highlights the strategies we utilised to manage a gravid patient presenting with nephrotic syndrome at 22 weeks gestation, where diagnosis could only be confirmed on renal biopsy in the postpartum period.
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Affiliation(s)
- Lucy Wang
- Nepean Hospital, Penrith, NSW, Australia
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Sun Y, Kronenberg NM, Sethi SK, Dash SN, Kovalik ME, Sempowski B, Strickland S, Raina R, Sperati CJ, Tian X, Ishibe S, Hall G, Gather MC. CRB2 Depletion Induces YAP Signaling and Disrupts Mechanosensing in Podocytes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.22.619513. [PMID: 39484460 PMCID: PMC11527017 DOI: 10.1101/2024.10.22.619513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Focal Segmental Glomerulosclerosis (FSGS) is a histologic lesion caused by a variety of injurious stimuli that lead to dysfunction/loss of glomerular visceral epithelial cells (i.e. podocytes). Pathogenic mutations in CRB2, encoding the type 1 transmembrane protein Crumb 2 Homolog Protein, have been shown to cause early-onset corticosteroid-resistant nephrotic syndrome (SRNS)/FSGS. Here, we identified a 2-generation East Asian kindred (DUK40595) with biopsy-proven SRNS/FSGS caused by a compound heterozygous mutation in CRB2 comprised of the previously described truncating mutation p.Gly1036_Alafs*43 and a rare 9-bp deletion mutation p.Leu1074_Asp1076del. Because compound heterozygous mutations involving the truncating p.Gly1036_Alafs*43 variant have been associated with reduced CRB2 expression in podocytes and autosomal recessive SRNS/FSGS, we sought to define the pathogenic effects of CRB2 deficiency in podocytes. We show that CRB2 knockdown induces YAP activity and target gene expression in podocytes. It upregulates YAP-mediated mechanosignaling and increases the density of focal adhesion and F-actin. Using Elastic Resonator Interference Stress Microscopy (ERISM), we demonstrate that CRB2 knockdown also enhances podocyte contractility in a substrate stiffness-dependent manner. The knockdown effect decreases with increasing substrate stiffness, indicating impaired mechanosensing in CRB2 knockdown cells at low substrate stiffness. While the mechanical activation of CRB2 knockdown cells is associated with increased YAP activity, the enhanced cell contractility is not significantly reduced by the selective YAP inhibitors K-975 and verteporfin, suggesting that multiple pathways may be involved in mechanosignaling downstream of CRB2. Taken together, these studies provide the first evidence that CRB2 deficiency may impair podocyte mechanotransduction via disruption of YAP signaling in podocytes.
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Affiliation(s)
- Yingyu Sun
- Humboldt Centre for Nano- and Biophotonics, Department of Chemistry, University of Cologne, Cologne, Germany
| | - Nils M. Kronenberg
- Humboldt Centre for Nano- and Biophotonics, Department of Chemistry, University of Cologne, Cologne, Germany
| | - Sidharth K. Sethi
- Pediatric Nephrology and Pediatric Kidney Transplantation, Medanta Kidney and Urology Institute, The Medicity Hospital, Gurgaon, Haryana, India
| | - Surjya N. Dash
- Division of Nephrology, Department of Medicine, Duke University, Durham, North Carolina, U.S.A
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, U.S.A
| | - Maria E. Kovalik
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, U.S.A
| | - Benjamin Sempowski
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, U.S.A
| | - Shelby Strickland
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, U.S.A
| | - Rupresh Raina
- Division of Nephrology, Department of Medicine, Yale University, New Haven, Connecticut, U.S.A
- Cleveland Clinic Akron General Medical Center, Akron Nephrology Associates, Akron, Ohio, USA
| | - C. John Sperati
- Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, U.S.A
| | - Xuefei Tian
- Cleveland Clinic Akron General Medical Center, Akron Nephrology Associates, Akron, Ohio, USA
| | - Shuta Ishibe
- Cleveland Clinic Akron General Medical Center, Akron Nephrology Associates, Akron, Ohio, USA
| | - Gentzon Hall
- Division of Nephrology, Department of Medicine, Duke University, Durham, North Carolina, U.S.A
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, U.S.A
| | - Malte C. Gather
- Humboldt Centre for Nano- and Biophotonics, Department of Chemistry, University of Cologne, Cologne, Germany
- Centre of Biophotonics, SUPA, School of Physics and Astronomy, University of St Andrews, St Andrews, U.K
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Disease (CECAD), University of Cologne, Cologne, Germany
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Chow AK, Guo Y, Mallipattu SK. Developing Krüppel-Like Factor 15 Agonists for Kidney Disease. J Am Soc Nephrol 2024; 35:1434-1437. [PMID: 39352761 PMCID: PMC11452166 DOI: 10.1681/asn.0000000000000417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2024] Open
Affiliation(s)
- Andrew K. Chow
- Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York
| | - Yiqing Guo
- Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York
| | - Sandeep K. Mallipattu
- Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York
- Renal Section, Northport VA Medical Center, Northport, New York
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Katafuchi E, Hisano S, Kurata S, Muta K, Uesugi N, Miyamoto T, Harada Y, Shimajiri S, Katafuchi R, Nakayama T. Aberrant localization of β1 integrin in podocyte cytoplasm of primary FSGS with cellular lesion. Virchows Arch 2024:10.1007/s00428-024-03919-0. [PMID: 39271482 DOI: 10.1007/s00428-024-03919-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 08/19/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024]
Abstract
Podocyte detachment is a major trigger in pathogenesis of focal segmental glomerulosclerosis (FSGS). Detachment via β1 integrin (ITGB1) endocytosis, associated with endothelial cell injury, has been reported in animal models but remains unknown in human kidneys. The objectives of our study were to examine the difference in ITGB1 dynamics between primary FSGS and minimal change nephrotic syndrome (MCNS), among variants of FSGS, as well as between the presence or absence of cellular lesions (CEL-L) in human kidneys, and to elucidate the pathogenesis of FSGS. Thirty-one patients with primary FSGS and 14 with MCNS were recruited. FSGS cases were categorized into two groups: those with CEL-L, defined by segmental endocapillary hypercellularity occluding lumina, and those without CEL-L. The podocyte cytoplasmic ITGB1 levels, ITGB1 expression, and degrees of podocyte detachment and subendothelial widening were compared between FSGS and MCNS, FSGS variants, and FSGS groups with and without CEL-L (CEL-L( +)/CEL-L( -)). ITGB1 distribution in podocyte cytoplasm was significantly greater in CEL-L( +) group than that in MCNS and CEL-L( -) groups. ITGB1 expression was similar in CEL-L( +) and MCNS, but lower in CEL-L( -) compared with others. Podocyte detachment levels were comparable in CEL-L( +) and CEL-L( -) groups, both exhibiting significantly higher detachment than the MCNS group. Subendothelial widening was significantly greater in CEL-L( +) compared with CEL-L( -) and MCNS groups. The findings of this study imply the existence of distinct pathological mechanisms associated with ITGB1 dynamics between CEL-L( +) and CEL-L( -) groups, and suggest a potential role of endothelial cell injury in the pathogenesis of cellular lesions in FSGS.
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Affiliation(s)
- Eisuke Katafuchi
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-Ku, Kitakyushu, 807-8555, Japan.
| | - Satoshi Hisano
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-Ku, Kitakyushu, 807-8555, Japan
| | - Satoko Kurata
- Department of Pediatrics and Child Health, School of Medicine, Kurume University, Kurume, Japan
| | - Kumiko Muta
- Department of Nephrology, Nagasaki University Hospital, Nagasaki, Japan
| | - Noriko Uesugi
- Department of Pathology, Fukuoka University School of Medicine, Fukuoka, Japan
| | - Tetsu Miyamoto
- Kidney Center, Hospital of the University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yoshikazu Harada
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-Ku, Kitakyushu, 807-8555, Japan
| | - Shohei Shimajiri
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-Ku, Kitakyushu, 807-8555, Japan
| | - Ritsuko Katafuchi
- Kidney Unit, National Hospital Organization Fukuokahigashi Medical Center, Fukuoka, Japan
- Kidney Unit, Medical Corporation Houshikai Kano Hospital, 1-2-1, Chuoekimae, Sjingu-Machi, Kasuya-Gun, Fukuoka, 811-0120, Japan
| | - Toshiyuki Nakayama
- Department of Pathology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-Ku, Kitakyushu, 807-8555, Japan
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11
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Fan Y, Dong S, Xia Y, Yang X, Lei Q, Xu F, Liang D, Liang S, Zhang M, Yang F, Jing Y, Li L, Zhu X, Bao H, Chen Z, Zeng C. Role of TSP-1 and its receptor ITGB3 in the renal tubulointerstitial injury of focal segmental glomerulosclerosis. J Biol Chem 2024; 300:107516. [PMID: 38960036 PMCID: PMC11339032 DOI: 10.1016/j.jbc.2024.107516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 05/17/2024] [Accepted: 06/02/2024] [Indexed: 07/05/2024] Open
Abstract
Focal segmental glomerulosclerosis (FSGS), a common cause of primary glomerulonephritis, has a poor prognosis and is pathologically featured by tubulointerstitial injury. Thrombospondin-1 (TSP-1) is an extracellular matrix protein that acts in combination with different receptors in the kidney. Here, we analyzed the tubular expression of TSP-1 and its receptor integrin β3 (ITGB3) in FSGS. Previously the renal interstitial chip analysis of FSGS patients with tubular interstitial injury showed that the expression of TSP-1 and ITGB3 were upregulated. We found that the expression of TSP-1 and ITGB3 increased in the tubular cells of FSGS patients. The plasma level of TSP-1 increased and was correlated to the degree of tubulointerstitial lesions in FSGS patients. TSP-1/ITGB3 signaling induced renal tubular injury in HK-2 cells exposure to bovine serum albumin and the adriamycin (ADR)-induced nephropathy model. THBS1 KO ameliorated tubular injury and renal fibrosis in ADR-treated mice. THBS1 knockdown decreased the expression of KIM-1 and caspase 3 in the HK-2 cells treated with bovine serum albumin, while THBS1 overexpression could induce tubular injury. In vivo, we identified cyclo-RGDfK as an agent to block the binding of TSP-1 to ITGB3. Cyclo-RGDfK treatment could alleviate ADR-induced renal tubular injury and interstitial fibrosis in mice. Moreover, TSP-1 and ITGB3 were colocalized in tubular cells of FSGS patients and ADR-treated mice. Taken together, our data showed that TSP-1/ITGB3 signaling contributed to the development of renal tubulointerstitial injury in FSGS, potentially identifying a new therapeutic target for FSGS.
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Affiliation(s)
- Yun Fan
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Medical University, Nanjing, China; the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China
| | - Shihui Dong
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yuanyuan Xia
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xue Yang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Qunjuan Lei
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China; Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Feng Xu
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Dandan Liang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Shaoshan Liang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Mingchao Zhang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Fan Yang
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Yan Jing
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Lijuan Li
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Xiaodong Zhu
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Hao Bao
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Zhaohong Chen
- National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Caihong Zeng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing Medical University, Nanjing, China; National Clinical Research Center for Kidney Diseases, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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12
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Velez JCQ, Thakker KM, Bensink ME, Lerma EV, Lieblich R, Bunke CM, Gong W, Wang K, Rava AR, Amari DT, Oliveri D, Murphy MV, Cork DM. Cardiovascular, Kidney Failure, and All-Cause Mortality Events in Patients with FSGS in a US Real-World Database. KIDNEY360 2024; 5:1145-1153. [PMID: 38748483 PMCID: PMC11371351 DOI: 10.34067/kid.0000000000000469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 05/03/2024] [Indexed: 08/30/2024]
Abstract
Key Points In our patients with FSGS, elevated proteinuria and progression to kidney failure (KF) were associated with a higher risk of cardiovascular disease/all-cause mortality events. In addition, elevated pre-KF proteinuria was associated with KF/all-cause mortality events. CKD stage, nephrotic syndrome, and cardiovascular disease event rates, as well as the incremental costs of these events, were high. Background FSGS leads to proteinuria and progressive decline in GFR, which correlates with kidney failure (KF) and increased cardiovascular risk. The purpose of this study was to estimate the effects of proteinuria on KF status/all-cause mortality and cardiovascular disease (CVD) events/all-cause mortality, as well as the relationship between progression to KF and occurrence of CVD/mortality events among adult patients (18 years or older) with FSGS. Methods This was an observational, retrospective cohort study utilizing Optum deidentified Market Clarity Data and proprietary Natural Language Processing data. The study period was from January 1, 2007, through March 31, 2021, with patients in the overall cohort being identified from July 1, 2007, through March 31, 2021. The index date was the first FSGS ICD-10 diagnosis code or FSGS-related natural language processing term within the identification period. Results Elevated proteinuria >1.5 and ≥3.5 g/g increased the risk of KF/all-cause mortality (adjusted hazard ratio [HR] [95% confidence interval (CI)], 2.34 [1.99 to 2.74] and 2.44 [2.09 to 2.84], respectively) and CVD/all-cause mortality (adjusted HR [95% CI], 2.11 [1.38 to 3.22] and 2.27 [1.44 to 3.58], respectively). Progression to KF was also associated with a higher risk of CVD/all-cause mortality (adjusted HR [95% CI], 3.04 [2.66 to 3.48]). Conclusions A significant proportion of patients with FSGS experience KF and CVD events. Elevated proteinuria and progression to KF were associated with a higher risk of CVD/all-cause mortality events, and elevated pre-KF proteinuria was associated with progression to KF/all-cause mortality events. Treatments that meaningfully reduce proteinuria and slow the decline in GFR have the potential to reduce the risk of CVD, KF, and early mortality in patients with FSGS.
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Affiliation(s)
- Juan Carlos Q. Velez
- Department of Nephrology, Ochsner Health, New Orleans, Louisiana
- Ochsner Clinical School, The University of Queensland, Brisbane, Queensland, Australia
| | | | | | - Edgar V. Lerma
- University of Illinois Chicago/Advocate Christ Medical Center, Oak Lawn, Illinois
| | | | | | - Wu Gong
- Travere Therapeutics, Inc., San Diego, California
| | - Kaijun Wang
- Travere Therapeutics, Inc., San Diego, California
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13
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Leal A, Magalhães M, Teles Pinto N. A Potentially Fatal Cause of Sciatica: A Rare Case of Nerve Compression Caused by a Pseudoaneurysm of the Renal Artery of a Transplanted Kidney. Cureus 2024; 16:e66130. [PMID: 39229393 PMCID: PMC11370988 DOI: 10.7759/cureus.66130] [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] [Accepted: 08/04/2024] [Indexed: 09/05/2024] Open
Abstract
Renal transplant is the gold standard treatment for end-stage kidney disease (ESKD). Despite the evolution of renal transplant procedures, complications can still occur. Transplant renal artery pseudoaneurysm is a rare but potentially life-threatening complication, which can be asymptomatic or cause mass-effect symptoms. We report an unusual case of a pseudoaneurysm of an unfunctional renal transplant that caused a femoral nerve compression, mimicking lumbosacral radiculopathy. The case concerns a 38-year-old woman with primary focal segmental glomerulosclerosis (FSGS) that progressed to ESKD. The patient underwent a kidney transplant that failed a few years after the surgery. More than 10 years later, she presented with symptoms consistent with lumbosacral radiculopathy, which was ultimately diagnosed as femoral nerve compression caused by a transplant renal artery pseudoaneurysm. This case emphasizes that each patient's medical history should always be considered when assessing even common complaints because rare causes can manifest in frequent symptoms. On the other hand, this case makes us reflect on weighing up the cost/benefit of some diagnostic investigations, as it is important not only to investigate the most common causes but also to rule out, in selected patients, those that, although rare, can be life-threatening.
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Affiliation(s)
- Andreia Leal
- Family Medicine, Unidade Local de Saúde de Santo António, Porto, PRT
| | - Mariana Magalhães
- Family Medicine, Unidade Local de Saúde de Santo António, Porto, PRT
| | - Nuno Teles Pinto
- Family Medicine, Unidade Local de Saúde de Santo António, Porto, PRT
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14
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Stamellou E, Nadal J, Hendry B, Mercer A, Bechtel-Walz W, Schiffer M, Eckardt KU, Kramann R, Moeller MJ, Floege J. Long-term outcomes of adults with FSGS in the German Chronic Kidney Disease cohort. Clin Kidney J 2024; 17:sfae131. [PMID: 38989280 PMCID: PMC11234294 DOI: 10.1093/ckj/sfae131] [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: 01/19/2024] [Indexed: 07/12/2024] Open
Abstract
Background Focal segmental glomerulosclerosis (FSGS) can lead to kidney failure in adults. This study examines the progression of FSGS in the German Chronic Kidney Disease (GCKD) cohort. Methods The GCKD study (N = 5217), a prospective cohort, included 159 patients with biopsy-confirmed FSGS recruited from 2010 to 2012. Baseline was defined as the first study visit. Adjudicated endpoints included a composite kidney endpoint (CKE), including an estimated glomerular filtration rate (eGFR) decrease >40%, eGFR <15 ml/min/1.73 m2 or initiation of kidney replacement therapy and combined major adverse cardiovascular events (MACE), including non-fatal myocardial infarction or stroke and all-cause mortality. Associations between baseline demographics, laboratory data, comorbidity and CKE and MACE were analysed using the Cox proportional hazards regression model. Results The mean age at baseline was 52.1 ± 13.6 years, with a disease duration of 4.72 years (quartile 1: 1; quartile 3: 6) before joining the study. The median urinary albumin:creatinine ratio (UACR) at baseline was 0.7 g/g (IQR 0.1;1.8), while mean eGFR was 55.8 ± 23 ml/min/1.73 m2. Based on clinical and pathological features, 69 (43.4%) patients were categorized as primary FSGS, 55 (34.6%) as secondary FSGS and 35 (22%) as indeterminate. Over a follow-up of 6.5 years, 44 patients reached the composite kidney endpoint and 16 individuals had at least one MACE. UACR ≥0.7 g/g was strongly associated with both the composite kidney endpoint {hazard ratio [HR] 5.27 [95% confidence interval (CI) 2.4-11.5]} and MACE [HR 3.37 (95% CI 1.05-10.82)] compared with <0.7 g/g, whereas a higher eGFR at baseline (per 10 ml/min) was protective for both endpoints [HR 0.8 (95% CI 0.68-0.95) and HR 0.63 (95% CI 0.46-0.88), respectively]. Patients with secondary FSGS experienced a greater rate of eGFR decline than patients with primary FSGS. Conclusions Lower eGFR and higher albuminuria are key risk factors for kidney disease progression and cardiovascular events in patients with FSGS.
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Affiliation(s)
- Eleni Stamellou
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
- Department of Nephrology, School of Medicine, University of Ioannina, Ioannina, Greece
| | - Jennifer Nadal
- Department of Medical Biometry, Informatics and Epidemiology, Faculty of Medicine, University Hospital Bonn, Bonn, Germany
| | | | | | - Wibke Bechtel-Walz
- Department of Medicine IV, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
- Berta‐Ottenstein Program, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Mario Schiffer
- Department of Nephrology and Hypertension, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Hypertension, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Rafael Kramann
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - Marcus J Moeller
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - Jürgen Floege
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
- Department of Cardiology, RWTH Aachen University Hospital, Aachen, Germany
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15
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Duret LC, Hamidouche T, Steers NJ, Pons C, Soubeiran N, Buret D, Gilson E, Gharavi AG, D'Agati VD, Shkreli M. Targeting WIP1 phosphatase promotes partial remission in experimental collapsing glomerulopathy. Kidney Int 2024; 105:980-996. [PMID: 38423182 DOI: 10.1016/j.kint.2024.02.009] [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: 09/08/2023] [Revised: 12/16/2023] [Accepted: 02/02/2024] [Indexed: 03/02/2024]
Abstract
Collapsing focal segmental glomerulosclerosis (FSGS), also known as collapsing glomerulopathy (CG), is the most aggressive variant of FSGS and is characterized by a rapid progression to kidney failure. Understanding CG pathogenesis represents a key step for the development of targeted therapies. Previous work implicated the telomerase protein component TERT in CG pathogenesis, as transgenic TERT expression in adult mice resulted in a CG resembling that seen in human primary CG and HIV-associated nephropathy (HIVAN). Here, we used the telomerase-induced mouse model of CG (i-TERTci mice) to identify mechanisms to inhibit CG pathogenesis. Inactivation of WIP1 phosphatase, a p53 target acting in a negative feedback loop, blocked disease initiation in i-TERTci mice. Repression of disease initiation upon WIP1 deficiency was associated with senescence enhancement and required transforming growth factor-β functions. The efficacy of a pharmacologic treatment to reduce disease severity in both i-TERTci mice and in a mouse model of HIVAN (Tg26 mice) was then assessed. Pharmacologic inhibition of WIP1 enzymatic activity in either the telomerase mice with CG or in the Tg26 mice promoted partial remission of proteinuria and ameliorated kidney histopathologic features. Histological as well as high-throughput sequencing methods further showed that selective inhibition of WIP1 does not promote kidney fibrosis or inflammation. Thus, our findings suggest that targeting WIP1 may be an effective therapeutic strategy for patients with CG.
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Affiliation(s)
- Lou C Duret
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France
| | - Tynhinane Hamidouche
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France
| | - Nicholas J Steers
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Catherine Pons
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France
| | - Nicolas Soubeiran
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France
| | - Delphine Buret
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France
| | - Eric Gilson
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France; International Laboratory in Hematology and Cancer, Shanghai Jiao Tong University School of Medicine/Ruijin Hospital/CNRS/INSERM/Nice University, Pôle Sino-Français de Recherche en Sciences du Vivant et Génomique, Shanghai Ruijin Hospital, Huangpu, Shanghai, PR China; Department of Genetics, CHU Nice, Nice, France
| | - Ali G Gharavi
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Vivette D D'Agati
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA
| | - Marina Shkreli
- Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS) UMR7284, Institut National de la Santé et de la Recherche Médicale (Inserm) U1081, Institute for Research on Cancer and aging, Nice (IRCAN), Nice, France.
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16
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Trachtman H, Radhakrishnan J, Rheault MN, Alpers CE, Barratt J, Heerspink HJ, Noronha IL, Perkovic V, Rovin B, Trimarchi H, Wong MG, Mercer A, Inrig J, Rote W, Murphy E, Bedard PW, Roth S, Bieler S, Komers R. Focal Segmental Glomerulosclerosis Patient Baseline Characteristics in the Sparsentan Phase 3 DUPLEX Study. Kidney Int Rep 2024; 9:1020-1030. [PMID: 38765567 PMCID: PMC11101813 DOI: 10.1016/j.ekir.2024.01.032] [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: 09/12/2023] [Revised: 01/11/2024] [Accepted: 01/15/2024] [Indexed: 05/22/2024] Open
Abstract
Introduction The phase 3 DUPLEX trial is evaluating sparsentan, a novel, nonimmunosuppressive, single-molecule dual endothelin angiotensin receptor antagonist, in patients with focal segmental glomerulosclerosis (FSGS). Methods DUPLEX (NCT03493685) is a global, multicenter, randomized, double-blind, parallel-group, active-controlled study evaluating the efficacy and safety of sparsentan 800 mg once daily versus irbesartan 300 mg once daily in patients aged 8 to 75 years (USA/UK) and 18 to 75 years (ex-USA/UK) weighing ≥20 kg with biopsy-proven FSGS or documented genetic mutation in a podocyte protein associated with FSGS, and urine protein-to-creatinine ratio (UP/C) ≥1.5 g/g. Baseline characteristics blinded to treatment allocation are reported descriptively. Results The primary analysis population includes 371 patients (336 adult, 35 pediatric [<18 years]) who were randomized and received study drug (median age, 42 years). Patients were White (73.0%), Asian (13.2%), Black/African American (6.7%), or Other race (7.0%); and from North America (38.8%), Europe (36.1%), South America (12.7%), or Asia Pacific (12.4%). Baseline median UP/C was 3.0 g/g; 42.6% in nephrotic-range (UP/C >3.5 g/g [adults]; >2.0 g/g [pediatrics]). Patients were evenly distributed across estimated glomerular filtration rate (eGFR) categories corresponding to chronic kidney disease (CKD) stages 1 to 3b. Thirty-three patients (9.4% of 352 evaluable samples) had pathogenic or likely pathogenic (P/LP) variants of genes essential to podocyte structural integrity and function, 27 (7.7%) had P/LP collagen gene (COL4A3/4/5) variants, and 14 (4.0%) had high-risk APOL1 genotypes. Conclusions Patient enrollment in DUPLEX, the largest interventional study in FSGS to date, will enable important characterization of the treatment effect of sparsentan in a geographically broad and clinically diverse FSGS population.
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Affiliation(s)
- Howard Trachtman
- Division of Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA
| | - Jai Radhakrishnan
- Division of Nephrology, Columbia University, New York, New York, USA
| | - Michelle N. Rheault
- Division of Pediatric Nephrology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Charles E. Alpers
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA
| | - Jonathan Barratt
- Department of Cardiovascular Sciences, University of Leicester General Hospital, Leicester, UK
| | - Hiddo J.L. Heerspink
- Department of Clinical Pharmacy and Pharmacology, University of Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- The George Institute for Global Health, Sydney, Australia
| | - Irene L. Noronha
- Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Vlado Perkovic
- Faculty of Medicine, University of New South Wales Sydney, Sydney, New South Wales, Australia
| | - Brad Rovin
- Division of Nephrology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Hernán Trimarchi
- Nephrology Service, Hospital Británico de Buenos Aires, Buenos Aires, Argentina
| | - Muh Geot Wong
- The George Institute for Global Health, Sydney, Australia
- Concord Clinical School, University of Sydney, Concord, New South Wales, Australia
| | | | - Jula Inrig
- Travere Therapeutics Inc., San Diego, California, USA
| | - William Rote
- Travere Therapeutics Inc., San Diego, California, USA
| | - Ed Murphy
- Travere Therapeutics Inc., San Diego, California, USA
| | | | - Sandra Roth
- Travere Therapeutics Inc., San Diego, California, USA
| | | | - Radko Komers
- Travere Therapeutics Inc., San Diego, California, USA
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17
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Mirioglu S, Daniel-Fischer L, Berke I, Ahmad SH, Bajema IM, Bruchfeld A, Fernandez-Juarez GM, Floege J, Frangou E, Goumenos D, Griffith M, Moran SM, van Kooten C, Steiger S, Stevens KI, Turkmen K, Willcocks LC, Kronbichler A. Management of adult patients with podocytopathies: an update from the ERA Immunonephrology Working Group. Nephrol Dial Transplant 2024; 39:569-580. [PMID: 38341276 PMCID: PMC11024823 DOI: 10.1093/ndt/gfae025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Indexed: 02/12/2024] Open
Abstract
The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are entities without immune complex deposits which can cause podocyte injury, thus are frequently grouped under the umbrella of podocytopathies. Whether MCD and FSGS may represent a spectrum of the same disease remains a matter of conjecture. Both frequently require repeated high-dose glucocorticoid therapy with alternative immunosuppressive treatments reserved for relapsing or resistant cases and response rates are variable. There is an unmet need to identify patients who should receive immunosuppressive therapies as opposed to those who would benefit from supportive strategies. Therapeutic trials focusing on MCD are scarce, and the evidence used for the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the management of glomerular diseases largely stems from observational and pediatric trials. In FSGS, the differentiation between primary forms and those with underlying genetic variants or secondary forms further complicates trial design. This article provides a perspective of the Immunonephrology Working Group (IWG) of the European Renal Association (ERA) and discusses the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases focusing on the management of MCD and primary forms of FSGS in the context of recently published evidence, with a special emphasis on the role of rituximab, cyclophosphamide, supportive treatment options and ongoing clinical trials in the field.
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Affiliation(s)
- Safak Mirioglu
- Division of Nephrology, Bezmialem Vakif University School of Medicine, Istanbul, Turkey
- Department of Immunology, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Lisa Daniel-Fischer
- Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
| | - Ilay Berke
- Division of Nephrology, Marmara University School of Medicine, Istanbul, Turkey
| | - Syed Hasan Ahmad
- Department of Renal Medicine, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK
| | - Ingeborg M Bajema
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands
| | - Annette Bruchfeld
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
- Department of Renal Medicine, Karolinska University Hospital and CLINTEC Karolinska Institutet, Stockholm, Sweden
| | | | - Jürgen Floege
- Division of Nephrology, RWTH Aachen University Hospital, Aachen, Germany
| | - Eleni Frangou
- Department of Nephrology, Limassol General Hospital, Limassol, Cyprus; University of Nicosia Medical School, Nicosia, Cyprus
| | - Dimitrios Goumenos
- Department of Nephrology and Renal Transplantation, Patras University Hospital, Patras, Greece
| | - Megan Griffith
- Imperial College Healthcare NHS Trust Renal and Transplant Centre, Hammersmith Hospital, London, United Kingdom
| | - Sarah M Moran
- Cork University Hospital, University College Cork, Cork, Ireland
| | - Cees van Kooten
- Division of Nephrology and Transplant Medicine, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Stefanie Steiger
- Division of Nephrology, Department of Internal Medicine IV, Hospital of the Ludwig-Maximilians-University, Munich, Germany
| | - Kate I Stevens
- Glasgow Renal and Transplant Unit, Queen Elizabeth University Hospital, Glasgow, UK
| | - Kultigin Turkmen
- Division of Nephrology, Department of Internal Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Lisa C Willcocks
- Department of Renal Medicine, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK
| | - Andreas Kronbichler
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria
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18
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Jafry NH, Manan S, Rashid R, Mubarak M. Clinicopathological features and medium-term outcomes of histologic variants of primary focal segmental glomerulosclerosis in adults: A retrospective study. World J Nephrol 2024; 13:88028. [PMID: 38596270 PMCID: PMC11000038 DOI: 10.5527/wjn.v13.i1.88028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 11/30/2023] [Accepted: 01/11/2024] [Indexed: 03/22/2024] Open
Abstract
BACKGROUND The Columbia classification identified five histological variants of focal segmental glomerulosclerosis (FSGS). The prognostic significance of these variants remains controversial. AIM To evaluate the relative frequency, clinicopathologic characteristics, and medium-term outcomes of FSGS variants at a single center in Pakistan. METHODS This retrospective study was conducted at the Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan on all consecutive adults (≥ 16 years) with biopsy-proven primary FSGS from January 1995 to December 2017. Studied subjects were treated with steroids as a first-line therapy. The response rates, doubling of serum creatinine, and kidney failure (KF) with replacement therapy were compared between histological variants using ANOVA or Kruskal Wallis, and Chi-square tests as appropriate. Data were analyzed by SPSS version 22.0. P-value ≤ 0.05 was considered significant. RESULTS A total of 401 patients were diagnosed with primary FSGS during the study period. Among these, 352 (87.7%) had a designated histological variant. The not otherwise specified (NOS) variant was the commonest, being found in 185 (53.9%) patients, followed by the tip variant in 100 (29.1%) patients. Collapsing (COL), cellular (CEL), and perihilar (PHI) variants were seen in 58 (16.9%), 6 (1.5%), and 3 (0.7%) patients, respectively. CEL and PHI variants were excluded from further analysis due to small patient numbers. The mean follow-up period was 36.5 ± 29.2 months. Regarding response rates of variants, patients with TIP lesions achieved remission more frequently (59.5%) than patients with NOS (41.8%) and COL (24.52%) variants (P < 0.001). The hazard ratio of complete response among patients with the COL variant was 0.163 [95% confidence interval (CI): 0.039-0.67] as compared to patients with NOS. The TIP variant showed a hazard ratio of 2.5 (95%CI: 1.61-3.89) for complete remission compared to the NOS variant. Overall, progressive KF was observed more frequently in patients with the COL variant, 43.4% (P < 0.001). Among these, 24.53% of patients required kidney replacement therapy (P < 0.001). The hazard ratio of doubling of serum creatinine among patients with the COL variant was 14.57 (95%CI: 1.87-113.49) as compared to patients with the TIP variant. CONCLUSION In conclusion, histological variants of FSGS are predictive of response to treatment with immunosuppressants and progressive KF in adults in our setup.
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Affiliation(s)
- Nazarul Hassan Jafry
- Department of Nephrology, Sindh Institute of Urology and Transplantation, Sindh, Karachi 74200, Pakistan
| | - Shumaila Manan
- Department of Nephrology, Sindh Institute of Urology and Transplantation, Sindh, Karachi 74200, Pakistan
| | - Rahma Rashid
- Department of Pathology, Sindh Institute of Urology and Transplantation, Sindh, Karachi 74200, Pakistan
| | - Muhammed Mubarak
- Department of Pathology, Sindh Institute of Urology and Transplantation, Sindh, Karachi 74200, Pakistan
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19
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de Zoysa N, Haruhara K, Nikolic-Paterson DJ, Kerr PG, Ling J, Gazzard SE, Puelles VG, Bertram JF, Cullen-McEwen LA. Podocyte number and glomerulosclerosis indices are associated with the response to therapy for primary focal segmental glomerulosclerosis. Front Med (Lausanne) 2024; 11:1343161. [PMID: 38510448 PMCID: PMC10951056 DOI: 10.3389/fmed.2024.1343161] [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: 11/23/2023] [Accepted: 02/19/2024] [Indexed: 03/22/2024] Open
Abstract
Corticosteroid therapy, often in combination with inhibition of the renin-angiotensin system, is first-line therapy for primary focal and segmental glomerulosclerosis (FSGS) with nephrotic-range proteinuria. However, the response to treatment is variable, and therefore new approaches to indicate the response to therapy are required. Podocyte depletion is a hallmark of early FSGS, and here we investigated whether podocyte number, density and/or size in diagnostic biopsies and/or the degree of glomerulosclerosis could indicate the clinical response to first-line therapy. In this retrospective single center cohort study, 19 participants (13 responders, 6 non-responders) were included. Biopsies obtained at diagnosis were prepared for analysis of podocyte number, density and size using design-based stereology. Renal function and proteinuria were assessed 6 months after therapy commenced. Responders and non-responders had similar levels of proteinuria at the time of biopsy and similar kidney function. Patients who did not respond to treatment at 6 months had a significantly higher percentage of glomeruli with global sclerosis than responders (p < 0.05) and glomerulosclerotic index (p < 0.05). Podocyte number per glomerulus in responders was 279 (203-507; median, IQR), 50% greater than that of non-responders (186, 118-310; p < 0.05). These findings suggest that primary FSGS patients with higher podocyte number per glomerulus and less advanced glomerulosclerosis are more likely to respond to first-line therapy at 6 months. A podocyte number less than approximately 216 per glomerulus, a GSI greater than 1 and percentage global sclerosis greater than approximately 20% are associated with a lack of response to therapy. Larger, prospective studies are warranted to confirm whether these parameters may help inform therapeutic decision making at the time of diagnosis of primary FSGS.
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Affiliation(s)
- Natasha de Zoysa
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
| | - Kotaro Haruhara
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
- Division of Nephrology and Hypertension, Jikei University School of Medicine, Tokyo, Japan
| | - David J. Nikolic-Paterson
- Department of Nephrology, Monash Medical Centre, Clayton, VIC, Australia
- Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia
| | - Peter G. Kerr
- Department of Nephrology, Monash Medical Centre, Clayton, VIC, Australia
- Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia
| | - Jonathan Ling
- Department of Nephrology, Monash Medical Centre, Clayton, VIC, Australia
- Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC, Australia
| | - Sarah E. Gazzard
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
| | - Victor G. Puelles
- III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
| | - John F. Bertram
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
- ARC Training Centre for Cell and Tissue Engineering Technologies, Melbourne, VIC, Australia
- ARC Training Centre for Cell and Tissue Engineering Technologies, Brisbane, QLD, Australia
| | - Luise A. Cullen-McEwen
- Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
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20
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Wang Y, Duan H, Yalikun Y, Cheng S, Li M. A pendulum-type electrochemical aptamer-based sensor for continuous, real-time and stable detection of proteins. Talanta 2024; 266:125026. [PMID: 37544252 DOI: 10.1016/j.talanta.2023.125026] [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: 04/24/2023] [Revised: 07/27/2023] [Accepted: 08/01/2023] [Indexed: 08/08/2023]
Abstract
Continuous detection of proteins is crucial for health management and biomedical research. Electrochemical aptamer-based (E-AB) sensor that relies on binding affinity between a recognition oligonucleotide and its specific target is a versatile platform to fulfill this purpose. Yet, the vast majority of E-AB sensors are characterized by voltammetric methods, which suffer from signal drifts and low-frequency data acquisition during continuous operations. To overcome these limitations, we developed a novel E-AB sensor empowered by Gold nanoparticle-DNA Pendulum (GDP). Using chronoamperometric interrogation, the developed sensor enabled drift-resistant, high-frequency, and real-time monitoring of vascular endothelial growth factor (VEGF), a vital signaling protein that regulates angiogenesis, endothelial cell proliferation and vasculogenesis. We assembled VEGF aptamer-anchored GDP probes to a reduced graphene modified electrode, where a fast chronoamperometric current transient occurs as the GDP rapidly transport to the electrode surface. In the presence of target molecules, longer and concentration-dependent time decays were observed because of slower motion of the GDP in its bound state. After optimizing several decisive parameters, including composition ratios of GDP, probe density, and incubation time, the GDP empowered E-AB sensor achieves continuous, selective, and reversible monitoring of VEGF in both phosphate buffered saline (PBS) solutions and artificial urine with a wide detection range from 13 fM to 130 nM. Moreover, the developed sensor acquires signals on a millisecond timescale, and remains resistant to signal degradation during operation. This study offers a new approach to designing E-AB architectures for continuous biomolecular monitoring.
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Affiliation(s)
- Yizhou Wang
- School of Engineering, Macquarie University, Sydney, 2109, NSW, Australia
| | - Haowei Duan
- School of Engineering, Macquarie University, Sydney, 2109, NSW, Australia
| | - Yaxiaer Yalikun
- Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, 630-0192, Ikoma, Japan
| | - Shaokoon Cheng
- School of Engineering, Macquarie University, Sydney, 2109, NSW, Australia
| | - Ming Li
- School of Engineering, Macquarie University, Sydney, 2109, NSW, Australia.
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21
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Lazarus B, Kitching AR. Hematuria in Podocytopathies: An Indicator of Poor Prognosis. Clin J Am Soc Nephrol 2024; 19:5-7. [PMID: 38051547 PMCID: PMC10843214 DOI: 10.2215/cjn.0000000000000383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2023]
Affiliation(s)
- Benjamin Lazarus
- Department of Nephrology, Monash Health, Clayton, Victoria, Australia
- Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia
| | - A. Richard Kitching
- Department of Nephrology, Monash Health, Clayton, Victoria, Australia
- Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia
- Department of Pediatric Nephrology, Monash Health, Clayton, Victoria, Australia
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22
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Miao J, Krisanapan P, Tangpanithandee S, Thongprayoon C, Mao MA, Cheungpasitporn W. Efficacy of extracorporeal plasma therapy for adult native kidney patients with Primary FSGS: a Systematic review. Ren Fail 2023; 45:2176694. [PMID: 36762994 PMCID: PMC9930861 DOI: 10.1080/0886022x.2023.2176694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
PURPOSE This study aimed to assess efficacy of extracorporeal plasma therapy (EPT), including plasmapheresis (PE), immunoadsorption (IA), low-density lipoprotein apheresis (LDL-A), and lymphocytapheresis (LCAP) for adult native kidney patients with primary focal segmental glomerulosclerosis (FSGS). METHODS A literature search was conducted using MEDLINE, EMBASE and Cochrane Databases through August 2022. Studies that reported outcomes of EPT in adult native kidneys with primary FSGS were enrolled. RESULTS 18 studies with 104 therapy-resistant or refractory primary native FSGS patients were identified. Overall EPT response rate was 56%, with long-term benefit of 46%. Of the 101 non-hemodialysis (HD) patients, 54% achieved remission, with 30% complete remission (CR) and 23% partial remission (PR). Of 31 patients with PE, response rate was 65%; CR and PR rates were 27% and 37% in 30 non-HD patients. Of 61 patients with LDL-A, the response rate was 54%; CR and PR rates were 41% and 3% in 29 non-HD patients. Of 10 patients with IA, response rate was 40%. Of 2 patients with LCAP, 1 achieved CR, and one developed renal failure. All 3 HD patients showed increase in urine output and gradual decrease in urine protein excretion following PE (n = 1) or LDL-A (n = 2). 2 of 3 HD patients ultimately discontinued dialysis. CONCLUSION EPT with immunosuppressive therapy showed benefit in some patients with refractory primary FSGS, and PE appeared to have a higher response rate.
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Affiliation(s)
- Jing Miao
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA,CONTACT Jing Miao Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Pajaree Krisanapan
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA,Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand,Division of Nephrology, Department of Internal Medicine, Thammasat University Hospital, Pathum Thani, Thailand
| | - Supawit Tangpanithandee
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Charat Thongprayoon
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Michael A. Mao
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Wisit Cheungpasitporn
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
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23
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Trachtman H, Diva U, Murphy E, Wang K, Inrig J, Komers R. Implications of Complete Proteinuria Remission at any Time in Focal Segmental Glomerulosclerosis: Sparsentan DUET Trial. Kidney Int Rep 2023; 8:2017-2028. [PMID: 37850006 PMCID: PMC10577371 DOI: 10.1016/j.ekir.2023.07.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 06/12/2023] [Accepted: 07/24/2023] [Indexed: 10/19/2023] Open
Abstract
Introduction Focal segmental glomerulosclerosis (FSGS) is a rare glomerular disease with high unmet clinical need. Interest in proteinuria as a surrogate end point for regulatory approval of novel treatments has increased. We assessed the relationship between achieving complete remission (CR) of proteinuria at least once during follow-up and long-term kidney outcomes. Methods This post hoc analysis included all patients enrolled in the DUET trial of sparsentan in FSGS and the open-label extension (OLE). Evaluations occurred every 12 weeks, including blood pressure (BP), edema, proteinuria, and kidney function. CR was defined as a urine protein/creatinine ratio ≤0.3g/g in a first morning urine sample. Results A total of 108 patients who received ≥1 sparsentan dose were included in this study. During a median follow-up of 47.0 months, 46 patients (43%) experienced ≥1 CR, 61% occurring within 12 months of starting sparsentan. There was an increased likelihood of CR with a higher sparsentan dose or baseline subnephrotic-range proteinuria. Achieving ≥1 CR was associated with significantly slower rate of estimated glomerular filtration rate (eGFR) decline versus non-CR patients (P < 0.05). Use of immunosuppressive agents was more frequent in patients who achieved a CR. However, the antiproteinuric effect of sparsentan was additive to that achieved with concomitant immunosuppressive treatment. No unanticipated adverse events occurred. Conclusion We conclude that sparsentan can be safely administered for extended periods and exerts a sustained antiproteinuric effect. Achievement of CR at any time during follow-up, even if it is not sustained, may be an indicator of a favorable response to treatment and a predictor of improved kidney function outcomes.
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Affiliation(s)
- Howard Trachtman
- Division of Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA
| | - Ulysses Diva
- Biometrics, Travere Therapeutics, Inc., San Diego, California, USA
| | - Edward Murphy
- Biometrics, Travere Therapeutics, Inc., San Diego, California, USA
| | - Kaijun Wang
- Biometrics, Travere Therapeutics, Inc., San Diego, California, USA
| | - Jula Inrig
- Nephrology, Travere Therapeutics, Inc., San Diego, California, USA
| | - Radko Komers
- Nephrology, Travere Therapeutics, Inc., San Diego, California, USA
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24
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Wada R, Kleijn HJ, Zhang L, Chen S. Population pharmacokinetic analysis of sparsentan in healthy volunteers and patients with focal segmental glomerulosclerosis. CPT Pharmacometrics Syst Pharmacol 2023; 12:1080-1092. [PMID: 37221817 PMCID: PMC10431048 DOI: 10.1002/psp4.12996] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 03/17/2023] [Accepted: 05/03/2023] [Indexed: 05/25/2023] Open
Abstract
Sparsentan is a single-molecule dual endothelin angiotensin receptor antagonist (DEARA) currently under investigation as a treatment for focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). A population pharmacokinetic (PK) analysis was performed to characterize the PKs of sparsentan and to evaluate the impact of FSGS disease characteristics and co-medications as covariates on sparsentan PKs. Blood samples were collected from 236 healthy volunteers, 16 subjects with hepatic impairment, and 194 primary and genetic FSGS patients enrolled in nine studies ranging from phase I to phase III. Sparsentan plasma concentrations were determined using validated liquid chromatography-tandem mass spectrometry with a lower limit of quantitation of 2 ng/mL. Modeling was conducted with the first-order conditional estimation with η-ϵ interaction (FOCE-1) method in NONMEM. A total of 20 covariates were tested using a univariate forward addition and stepwise backward elimination analysis with significance level of p < 0.01 and p < 0.001, respectively. A two-compartment model with first-order absorption and an absorption lag time with proportional plus additive residual error (2 ng/mL) described sparsentan PKs. A 32% increase of clearance due to CYP3A auto-induction occurred at steady-state. Covariates retained in the final model included formulation, cytochrome P450 (CYP) 3A4 inhibitor co-administration, sex, race, creatinine clearance, and serum alkaline phosphatase. Moderate and strong CYP3A4 inhibitors comedications increased area under the concentration-time curve by 31.4% and 191.3%, respectively. This population PK model of sparsentan suggests that dose adjustments may be warranted for patients taking moderate and strong CYP3A4 inhibitors concomitantly, but other covariates analyzed may not require dose adjustments.
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Affiliation(s)
| | | | - Lu Zhang
- Certara, Inc.Menlo ParkCaliforniaUSA
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25
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Milki AA, Bechara M, Lew SQ, Poon AN. Chronic Kidney Disease of Non-traditional Etiology in a Young Man From Central America: Geography, Poverty, and Uncertain Pathophysiology Create a Formidable Medical Challenge. Cureus 2023; 15:e38876. [PMID: 37303355 PMCID: PMC10257359 DOI: 10.7759/cureus.38876] [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] [Accepted: 05/11/2023] [Indexed: 06/13/2023] Open
Abstract
A man in his early 20s with kidney biopsy-confirmed focal segmental glomerulosclerosis (FSGS) was admitted with one month of nausea and vomiting, intermittent episodes of confusion, shortness of breath, and dysuria. He reported that many people from his native village in Central America, where he harvested sugarcane as a child, have died from kidney disease, including his father and cousin. He believed the source of disease to be agrochemicals found in the village's water supply. Although FSGS would be a rare manifestation, the patient's risk factors strongly suggested chronic kidney disease of unknown etiology (CKDu) - also known as Mesoamerican nephropathy (MeN) - a phenomenon he had never previously heard of. He took lisinopril for the last six years to manage his kidney disease. Due to uremic symptoms and abnormal electrolytes, he was initiated on hemodialysis.
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Affiliation(s)
- Anthony A Milki
- Department of Medicine, George Washington University School of Medicine and Health Sciences, Washington, USA
| | - Michael Bechara
- Department of Medicine, Division of Hospital Medicine, Virginia Hospital Center, Arlington, USA
| | - Susie Q Lew
- Department of Medicine, Division of Kidney Disease and Hypertension, George Washington University School of Medicine and Health Sciences, Washington, USA
| | - Adrienne N Poon
- Department of Medicine, Division of Hospital Medicine, George Washington University School of Medicine and Health Sciences, Washington, USA
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26
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Albandak M, Ayyad M, Abu Ajamia S, Quntar A, Al-Karaja L, Alsaid HM, Alamlih L. Rheumatoid Arthritis With Focal Segmental Glomerulosclerosis: A Case Report and Literature Review. Cureus 2023; 15:e37161. [PMID: 37153240 PMCID: PMC10161944 DOI: 10.7759/cureus.37161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/05/2023] [Indexed: 04/08/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease primarily affecting the joints and, to a lesser extent, other systems. Renal involvement in RA is rare and might be due to the presence of systemic inflammation or the toxic effect of the medications used. Of the many types of renal diseases that can affect RA patients, focal segmental glomerulosclerosis (FSGS) is rarely encountered. In this report, we present a rare co-existence of RA and FSGS in a 50-year-old female with RA who was found to have FSGS as a possible cause of proteinuria and an extraarticular manifestation of RA. The patient's RA started as palindromic rheumatism, which progressed later to chronic symmetrical polyarthritis of the small and large joints. Along with the flare of her joint disease, she was found to have lower limb edema. Her workup showed persistent proteinuria of more than one gram per day. Renal biopsy showed unexpected findings of FSGS. Our patient was treated with tapering doses of steroids, methotrexate, candesartan, and a diuretic that controlled joint disease, blood pressure, and proteinuria. Follow-up at two years showed normal kidney function tests, a significant decline in proteinuria, and controlled joint disease. Our case portrays a possible relationship between FSGS as a cause of proteinuria in patients with RA. Physicians should be aware of the possibility of FSGS in RA patients, which can affect the management plan, medication efficacy, and overall prognosis.
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27
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Amer F, Syed M, Afzal A, Hussain M, Hassan U, Bashir S, Hameed M, Ishtiaq S. IgM and C3 Deposition in Primary Focal Segmental Glomerulosclerosis (FSGS): A Clinical and Histopathological Spectrum. Cureus 2023; 15:e37346. [PMID: 37182061 PMCID: PMC10169510 DOI: 10.7759/cureus.37346] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/05/2023] [Indexed: 05/16/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a common renal disorder, characterized by progressive segmental sclerosis of renal glomeruli and clinical symptoms corresponding to proteinuria. Classically, it is not considered to be an antibody-mediated disease, however, IgM and C3 deposition may be seen in a subset of cases of FSGS. The impact of this immune deposition on histopathological features in renal core biopsies, on the urinary biochemical parameters, and the clinical outcomes, has not been previously investigated in our population. The aim of this study is to analyze the aforementioned parameters in patients with primary FSGS having antibody deposition as compared to those who do not have any antibody deposition. Some 155 patients diagnosed with FSGS were retrospectively enrolled in our study. The renal biopsies were reviewed for histopathological features and immunofluorescence (IF) findings of IgM and C3 glomerular deposition. These histological features were then compared with the biochemical parameters as well as the clinical outcomes of patients. The patients were assigned to Groups 1 and 2 based on the IF findings. The IgM and/or C3 glomerular deposition had a low incidence in patients with primary FSGS in our study (28.3%). Patients having IgM and C3 co-deposition had a significantly longer time duration since the onset of their clinical symptoms; active disease duration (42 months vs 22 months, p=0.049). The mean pre-treatment serum creatinine of patients with IgM and C3 co-deposition was 6.00 mg/dL as compared to 3.29 mg/dL in patients with no immune deposition (p=0.037). The immune deposition was associated with higher rates of segmental and global glomerulosclerosis, but this finding along with other evaluated histological parameters did not show statistical significance. The number of patients having IgM and/or C3 deposition and with active steroid use/renal dialysis was similar to patients having no IgM and/or C3 deposition. The IgM and/or C3 deposition in FSGS has a low incidence within and is not associated with any significant differences in histological parameters on renal core biopsies of patients from the Pakistani population. IgM and/or C3 deposition is also associated with a significantly longer duration of active disease and these patients may present with higher pre-treatment serum creatinine. Other biochemical parameters and clinical outcomes appear comparable between the groups based on the available clinical data.
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Affiliation(s)
- Faizan Amer
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
| | - Madiha Syed
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
| | | | - Mudassar Hussain
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
| | - Usman Hassan
- Pathology, Shaukat Khanum Memoiral Cancer Hospital and Research Centre, Lahore, PAK
| | - Shaarif Bashir
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
| | - Maryam Hameed
- Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, PAK
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28
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Egbuna O, Zimmerman B, Manos G, Fortier A, Chirieac MC, Dakin LA, Friedman DJ, Bramham K, Campbell K, Knebelmann B, Barisoni L, Falk RJ, Gipson DS, Lipkowitz MS, Ojo A, Bunnage ME, Pollak MR, Altshuler D, Chertow GM. Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants. N Engl J Med 2023; 388:969-979. [PMID: 36920755 DOI: 10.1056/nejmoa2202396] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
Abstract
BACKGROUND Persons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 (APOL1) are at greater risk for the development of rapidly progressive, proteinuric nephropathy. Despite the known genetic cause, therapies targeting proteinuric kidney disease in persons with two APOL1 variants (G1 or G2) are lacking. METHODS We used tetracycline-inducible APOL1 human embryonic kidney (HEK293) cells to assess the ability of a small-molecule compound, inaxaplin, to inhibit APOL1 channel function. An APOL1 G2-homologous transgenic mouse model of proteinuric kidney disease was used to assess inaxaplin treatment for proteinuria. We then conducted a single-group, open-label, phase 2a clinical study in which inaxaplin was administered to participants who had two APOL1 variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria (urinary protein-to-creatinine ratio of ≥0.7 to <10 [with protein and creatinine both measured in grams] and an estimated glomerular filtration rate of ≥27 ml per minute per 1.73 m2 of body-surface area). Participants received inaxaplin daily for 13 weeks (15 mg for 2 weeks and 45 mg for 11 weeks) along with standard care. The primary outcome was the percent change from the baseline urinary protein-to-creatinine ratio at week 13 in participants who had at least 80% adherence to inaxaplin therapy. Safety was also assessed. RESULTS In preclinical studies, inaxaplin selectively inhibited APOL1 channel function in vitro and reduced proteinuria in the mouse model. Sixteen participants were enrolled in the phase 2a study. Among the 13 participants who were treated with inaxaplin and met the adherence threshold, the mean change from the baseline urinary protein-to-creatinine ratio at week 13 was -47.6% (95% confidence interval, -60.0 to -31.3). In an analysis that included all the participants regardless of adherence to inaxaplin therapy, reductions similar to those in the primary analysis were observed in all but 1 participant. Adverse events were mild or moderate in severity; none led to study discontinuation. CONCLUSIONS Targeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two APOL1 variants and focal segmental glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.).
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Affiliation(s)
- Ogo Egbuna
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Brandon Zimmerman
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - George Manos
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Anne Fortier
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Madalina C Chirieac
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Leslie A Dakin
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - David J Friedman
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Kate Bramham
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Kirk Campbell
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Bertrand Knebelmann
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Laura Barisoni
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Ronald J Falk
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Debbie S Gipson
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Michael S Lipkowitz
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Akinlolu Ojo
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Mark E Bunnage
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Martin R Pollak
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - David Altshuler
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
| | - Glenn M Chertow
- From Vertex Pharmaceuticals (O.E., B.Z., G.M., A.F., M.C.C., L.A.D., M.E.B., D.A.), and Beth Israel Deaconess Medical Center, Harvard Medical School (D.J.F., M.R.P.) - both in Boston; King's College London, London (K.B.); Icahn School of Medicine at Mount Sinai, New York (K.C.); Necker Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.K.); Duke University, Durham (L.B.), and the University of North Carolina at Chapel Hill, Chapel Hill (R.J.F.) - both in North Carolina; the University of Michigan, Ann Arbor (D.S.G.); Georgetown University Hospital, Washington, DC (M.S.L.); University of Kansas School of Medicine, Kansas City (A.O.); and Stanford University School of Medicine, Palo Alto, CA (G.M.C.)
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STAT-3 signaling role in an experimental model of nephropathy induced by doxorubicin. Mol Cell Biochem 2022; 478:981-989. [PMID: 36201104 DOI: 10.1007/s11010-022-04574-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 09/23/2022] [Indexed: 01/10/2023]
Abstract
The focal segmental glomerulosclerosis (FSGS) is one of the most frequent glomerulopathy in the world, being considered a significative public health problem worldwide. The disease is characterized by glomerular loss mainly due to inflammation process and collagen fibers deposition. STAT-3 is a transcription factor associated with cell differentiation, migration and proliferation and in renal cells it has been related with fibrosis, acting on the progression of the lesion. Considering this perspective, the present study evaluated the involvement of STAT-3 molecule in an experimental model of FSGS induced by Doxorubicin (DOX). DOX mimics primary FSGS by causing both glomerular and tubular lesions and the inhibition of the STAT3 pathway leads to a decrease in fibrosis and attenuation of kidney damage. We described here a novel FSGS experimental model in a strain of genetically heterogeneous mice which resembles the reality of FSGS patients. DOX-injected mice presented elevated indices of albuminuria and glycosuria, that were significantly reduced in animals treated with a STAT-3 inhibitor (STATTIC), in addition with a decrease of some inflammatory molecules. Moreover, we detected that SOCS-3 (a regulator of STAT family) was up-regulated only in STATTIC-treated mice. Finally, histopathological analyzes showed that DOX-treated group had a significant increase in a tubulointerstitial fibrosis and tubular necrosis, which were not identified in both control and STATTIC groups. Thus, our results indicate that STAT-3 pathway possess an important role in experimental FSGS induced by DOX and may be an important molecule to be further investigated.
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Muacevic A, Adler JR. Tip-Variant Focal Segmental Glomerulosclerosis in a Patient With Primary Hypothyroidism: A Case Report. Cureus 2022; 14:e30020. [PMID: 36348899 PMCID: PMC9637278 DOI: 10.7759/cureus.30020] [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] [Accepted: 10/07/2022] [Indexed: 11/17/2022] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome (NS) and one of the leading causes of end-stage kidney disease. Endocrinological abnormalities due to the urinary loss of hormone-binding proteins, such as transient hypothyroidism, are well documented in FSGS. Secondary FSGS can arise due to viral infections, drugs, and pre-existing glomerular diseases. Few reports have highlighted the occurrence of FSGS in the background of hypothyroidism. We present a case of a young male with primary hypothyroidism who developed the tip variant of FSGS. A combination of oral corticosteroids and angiotensin-converting enzyme (ACE) inhibitors was successful in causing remission of the FSGS with no relapse.
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Gómez Preciado F, De Carvalho Ovalles RA, Codina S, Donadeu L, Favà A, Martinez Valenzuela L, Sandoval D, Fernández-Cidón B, Bestard O, Alia-Ramos P, Gomà M, Melilli E, Cruzado JM. Collapsing Glomerulonephritis in a Kidney Transplant Recipient after mRNA SARS-CoV-2 Vaccination. J Clin Med 2022; 11:jcm11133651. [PMID: 35806939 PMCID: PMC9267596 DOI: 10.3390/jcm11133651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 06/20/2022] [Accepted: 06/23/2022] [Indexed: 11/16/2022] Open
Abstract
With the vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), studies are describing cases of glomerulonephritis arising after vaccination. We present the first case of a kidney transplant patient who, after mRNA vaccination against SARS-CoV-2, developed nephrotic proteinuria and renal dysfunction, with a biopsy diagnostic of collapsing glomerulonephritis. No other triggers for this glomerulonephritis were identified. Antibodies against the spike protein were negative, but the patient developed a specific T-cell response. The close time between vaccination and the proteinuria suggests a possible determinant role of vaccination. We should be aware of nephropathies appearing after COVID-19 vaccination in kidney transplant recipients also.
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Affiliation(s)
- Francisco Gómez Preciado
- Department of Nephrology, Hospital Universitari de Bellvitge (HUB), 08907 Barcelona, Spain; (F.G.P.); (S.C.); (A.F.); (L.M.V.); (D.S.)
| | | | - Sergi Codina
- Department of Nephrology, Hospital Universitari de Bellvitge (HUB), 08907 Barcelona, Spain; (F.G.P.); (S.C.); (A.F.); (L.M.V.); (D.S.)
| | - Laura Donadeu
- Laboratory of Nephrology and Transplantation, Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain;
| | - Alexandre Favà
- Department of Nephrology, Hospital Universitari de Bellvitge (HUB), 08907 Barcelona, Spain; (F.G.P.); (S.C.); (A.F.); (L.M.V.); (D.S.)
| | - Laura Martinez Valenzuela
- Department of Nephrology, Hospital Universitari de Bellvitge (HUB), 08907 Barcelona, Spain; (F.G.P.); (S.C.); (A.F.); (L.M.V.); (D.S.)
| | - Diego Sandoval
- Department of Nephrology, Hospital Universitari de Bellvitge (HUB), 08907 Barcelona, Spain; (F.G.P.); (S.C.); (A.F.); (L.M.V.); (D.S.)
| | - Bárbara Fernández-Cidón
- Clinical Laboratory, IDIBELL-Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (B.F.-C.); (P.A.-R.)
| | - Oriol Bestard
- Kidney Transplant Unit, Nephrology Department, Vall d’Hebron Hospital Universitari, 08035 Barcelona, Spain;
| | - Pedro Alia-Ramos
- Clinical Laboratory, IDIBELL-Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, 08908 Barcelona, Spain; (B.F.-C.); (P.A.-R.)
| | - Montserrat Gomà
- Pathology Department, Hospital Universitari de Bellvitge (HUB), 08907 Barcelona, Spain; (R.A.D.C.O.); (M.G.)
| | - Edoardo Melilli
- Department of Nephrology, Hospital Universitari de Bellvitge (HUB), 08907 Barcelona, Spain; (F.G.P.); (S.C.); (A.F.); (L.M.V.); (D.S.)
- Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, L’Hospitalet de Llobregat, 08907 Barcelona, Spain
- Correspondence: (E.M.); (J.M.C.)
| | - Josep M Cruzado
- Department of Nephrology, Hospital Universitari de Bellvitge (HUB), 08907 Barcelona, Spain; (F.G.P.); (S.C.); (A.F.); (L.M.V.); (D.S.)
- Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, L’Hospitalet de Llobregat, 08907 Barcelona, Spain
- School of Medicine and Health Sciencies, University of Barcelona, L’Hospitalet de Llobregat, 08907, Barcelona, Spain
- Correspondence: (E.M.); (J.M.C.)
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Diagnosis and Treatment of Patients With FSGS/SRNS: A Delphi Survey. Kidney Int Rep 2022; 7:2081-2085. [PMID: 36090486 PMCID: PMC9458994 DOI: 10.1016/j.ekir.2022.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/03/2022] [Accepted: 06/13/2022] [Indexed: 11/20/2022] Open
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Sedlacek M, Pettus JR. Complete remission of tip lesion variant focal segmental glomerulosclerosis (FSGS) with the Janus Kinase (JAK) inhibitor tofacitinib. CEN Case Rep 2022; 11:225-230. [PMID: 34741283 PMCID: PMC9061925 DOI: 10.1007/s13730-021-00658-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 10/22/2021] [Indexed: 12/27/2022] Open
Abstract
A 67-year-old woman with transverse myelitis and seizure disorder secondary to suspected central nervous system (CNS) systemic lupus erythematosus (SLE) and seropositive rheumatoid arthritis had two episodes of severe nephrotic syndrome 15 years apart. She underwent a renal biopsy in both episodes, showing tip lesion variant focal segmental glomerulosclerosis (FSGS). The patient responded both times to prednisone treatment, achieving a complete remission within 2 months in the first episode and remission 4 months in the second episode. A year after her second episode, the patient had a third episode of severe nephrotic syndrome. She achieved an equally rapid complete remission in 3 months without steroid treatment, as she was concomitantly treated with the Janus Kinase (JAK) inhibitor tofacitinib for a flare of rheumatoid arthritis. This case report suggests that JAK inhibitors may have therapeutic use in FSGS, which is supported by experimental data in the medical literature.
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Affiliation(s)
- Martin Sedlacek
- Division of Nephrology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756-0001 USA
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA
| | - Jason R. Pettus
- Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756-0001 USA
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Efficacy and Safety of ACE Inhibitor and Angiotensin Receptor Blocker Therapies in Primary Focal Segmental Glomerulosclerosis Treatment: A Systematic Review and Meta-analysis. Kidney Med 2022; 4:100457. [PMID: 35518835 PMCID: PMC9065901 DOI: 10.1016/j.xkme.2022.100457] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Rationale and Objective Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy (renin-angiotensin-aldosterone system [RAAS] inhibitor) to control proteinuria in primary and genetic focal segmental glomerulosclerosis (FSGS) follows guidelines based on other proteinuria-related kidney diseases. There is no consensus on the efficacy and safety of RAAS inhibitor therapies in primary and genetic FSGS. This systematic review assessed the effects of RAAS inhibitor therapy on kidney outcomes in these patients. Study Design Systematic review of randomized controlled trials, interventional nonrandomized studies, observational studies, and retrospective studies. Setting & Study Populations Patients with primary and genetic FSGS. Selection Criteria for Studies PubMed, Cochrane Library, and Embase. Data Extraction 2 investigators independently screened studies and extracted data. Analytical Approach Results were summarized as the ratio of means (ROM) between baseline and follow-up measurements or as the hazard ratio using random-effects models. Results 30 publications were selected; 5 were controlled trials (4 randomized controlled trials). 8 assessed RAAS inhibitor monotherapy, while the rest studied RAAS inhibitors in combination with other drugs, mainly immunosuppressants. On average, a 32% proteinuria reduction (ROM, 0.68; 95% CI, 0.47-0.98) and no change in creatinine clearance (ROM, 0.95; 95% CI, 0.77-1.16) from baseline to the last reported follow-up was observed in patients treated with RAAS inhibitor monotherapy. When a RAAS inhibitor was combined with other drugs, a 72% proteinuria reduction was observed from baseline to the last reported follow-up (ROM, 0.24; 95% CI, 0.08-0.75). The published data did not allow for the assessment of the effects of RAAS inhibitor monotherapy on estimated glomerular filtration rate and end-stage kidney disease risks. Limitations Large study heterogeneity in design, patient populations, and treatment regimens. No access to individual patient-level data. Conclusions This review supports the tendency to observe a proteinuria reduction with RAAS inhibitors in patients with primary FSGS. RAAS inhibitor monotherapy was associated with maintained kidney function, as shown by no change in creatinine clearance. Strong evidence to quantify the effects of RAAS inhibitor monotherapy on end-stage kidney disease and glomerular filtration rate was lacking. Larger, well-designed clinical trials are needed to better understand the effects of RAAS inhibitors on primary FSGS.
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Hall G, Lin J. Outscoring Current Classification Systems for Nephrotic Syndrome. Am J Kidney Dis 2022; 79:783-784. [PMID: 35153081 DOI: 10.1053/j.ajkd.2021.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 12/19/2021] [Indexed: 11/11/2022]
Affiliation(s)
- Gentzon Hall
- Division of Nephrology, Department of Internal Medicine, Duke University School of Medicine, Durham, North Carolina; Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Jennie Lin
- Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois.
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Kidney tubule iron loading in experimental focal segmental glomerulosclerosis. Sci Rep 2022; 12:1199. [PMID: 35075227 PMCID: PMC8786831 DOI: 10.1038/s41598-022-05261-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/03/2022] [Indexed: 11/10/2022] Open
Abstract
Kidney iron deposition may play a role in the progression of tubulointerstitial injury during chronic kidney disease. Here, we studied the molecular mechanisms of kidney iron loading in experimental focal segmental glomerulosclerosis (FSGS) and investigated the effect of iron-reducing interventions on disease progression. Thy-1.1 mice were injected with anti-Thy-1.1 monoclonal antibody (mAb) to induce proteinuria. Urine, blood and tissue were collected at day (D)1, D5, D8, D15 and D22 after mAb injection. Thy-1.1 mice were subjected to captopril (CA), iron-deficient (ID) diet or iron chelation (deferoxamine; DFO). MAb injection resulted in significant albuminuria at all time points (p < 0.01). Kidney iron loading, predominantly in distal tubules, increased in time, along with urinary kidney injury molecule-1 and 24p3 concentration, as well as kidney mRNA expression of Interleukin-6 (Il-6) and Heme oxygenase-1 (Ho-1). Treatment with CA, ID diet or DFO significantly reduced kidney iron deposition at D8 and D22 (p < 0.001) and fibrosis at D22 (p < 0.05), but not kidney Il-6. ID treatment increased kidney Ho-1 (p < 0.001). In conclusion, kidney iron accumulation coincides with progression of tubulointerstitial injury in this model of FSGS. Reduction of iron loading halts disease progression. However, targeted approaches to prevent excessive kidney iron loading are warranted to maintain the delicate systemic and cellular iron balance.
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Varghese R, Majumdar A. A New Prospect for the Treatment of Nephrotic Syndrome Based on Network Pharmacology Analysis. Curr Res Physiol 2022; 5:36-47. [PMID: 35098155 PMCID: PMC8783131 DOI: 10.1016/j.crphys.2021.12.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 11/10/2021] [Accepted: 12/29/2021] [Indexed: 12/11/2022] Open
Abstract
Network pharmacology is an emerging field which is currently capturing interest in drug discovery and development. Chronic kidney conditions have become a threat globally due to its associated lifelong therapies. Nephrotic syndrome (NS) is a common glomerular disease that is seen in paediatric and adult population with characteristic manifestation of proteinuria, oedema, hypoalbuminemia, and hyperlipidemia. It involves podocyte damage with tubulointerstitial fibrosis and glomerulosclerosis. Till date there has been no specific treatment available for this condition that provides complete remission. Repurposing of drugs can thus be a potential strategy for the treatment of NS. Recently, epigenetic mechanisms were identified that promote progression of many renal diseases. Therefore, in the present study, we investigated two epigenetic drugs valproic acid (VPA) and all-trans retinoic acid (ATRA). Epigenetic drugs act by binging about changes in gene expression without altering the DNA sequence. The changes include DNA methylation or histone modifications. The targets for the two drugs ATRA and VPA were collated from ChEMBL and Binding DB. All the genes associated with NS were collected from DisGeNET and KEGG database. Interacting proteins for the target genes were acquired from STRING database. The genes were then subjected to gene ontology and pathway enrichment analysis using a functional enrichment software tool. A drug-target and drug-potential target-protein interaction network was constructed using the Cytoscape software. Our results revealed that the two drugs VPA and ATRA had 65 common targets that contributed to kidney diseases. Out of which, 25 targets were specifically NS associated. Further, our work exhibited that ATRA and VPA were synergistically involved in pathways of inflammation, renal fibrosis, glomerulosclerosis and possibly mitochondrial biogenesis and endoplasmic reticulum stress. We thus propose a synergistic potential of the two drugs for treating chronic kidney diseases, specifically NS. The outcomes will undoubtedly invigorate further preclinical and clinical explorative studies. We identify network pharmacology as an initial inherent approach in identifying drug candidates for repurposing and synergism.
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Affiliation(s)
- Rini Varghese
- Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, Maharashtra, 400098, India
| | - Anuradha Majumdar
- Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, Maharashtra, 400098, India
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Kidney Transplantation for Focal Segmental Glomerulosclerosis: Can We Prevent Its Recurrence? Personal Experience and Literature Review. J Clin Med 2021; 11:jcm11010093. [PMID: 35011834 PMCID: PMC8745094 DOI: 10.3390/jcm11010093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 11/17/2022] Open
Abstract
Background: Primary focal segmental glomerulosclerosis (FSGS) is associated with a high risk of recurrence after kidney transplantation with a major risk of graft loss despite preventive or curative treatments. Aim: to assess graft survival in FSGS kidney-transplant recipients and to compare those that had a relapse with those that had no relapse. Patients/Methods: we included 17 FSGS kidney-transplant recipients between January 2000 and January 2020, separated retrospectively into two groups (recurrences: n = 8 patients; no recurrences: n = 9 patients). FSGS recurrence was defined as having proteinuria of ≥3 g/g or urinary creatinine of ≥3 g/day. All patients received an induction therapy; maintenance immunosuppressive therapy at post-transplantation relied on tacrolimus/mycophenolate mofetil/steroids. In order to prevent or treat FSGS recurrence, patients received apheresis sessions plus rituximab. Results: FSGS recurrence rate was 47%. All patients that relapsed with a first graft also relapsed with subsequent grafts. Median time to recurrence was 3 (min: 1; max: 4745) days, despite rituximab/apheresis prophylaxis. Mean age was significantly lower in the relapsers (group 1) than in the non-relapsers (group 2); i.e., 47 ± 11 vs. 58 ± 9 years (p = 0.04). Time to progression to stage 5 chronic kidney disease (CKD) and young age at FSGS diagnosis were lower in group 1 compared to group 2; i.e., 5 (min: 1; max: 26) vs. 2 (min: 1; max: 26) years, and 16 (min: 4; max: 55) vs. 34 (min: 6; max 48) years, respectively. There was no difference between the two groups in terms of progression to CKD stage 5 on the native kidneys, averaging 7 years in both groups (p = 0.99). In group 1, seven patients received rituximab/apheresis prophylaxis, although this did not prevent the recurrence of FSGS. Conclusion: pretransplant prophylaxis with plasmapheresis/rituximab did not appear to reduce the risk of recurrence of primary FSGS on the graft, but could allow remission in the event of recurrence.
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Wang L, Tang Y, Buckley AF, Spurney RF. Blockade of the natriuretic peptide clearance receptor attenuates proteinuria in a mouse model of focal segmental glomerulosclerosis. Physiol Rep 2021; 9:e15095. [PMID: 34755480 PMCID: PMC8578888 DOI: 10.14814/phy2.15095] [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: 09/01/2021] [Revised: 09/23/2021] [Accepted: 09/23/2021] [Indexed: 12/31/2022] Open
Abstract
Glomerular podocytes play a key role in proteinuric diseases. Accumulating evidence suggests that cGMP signaling has podocyte protective effects. The major source of cGMP generation in podocytes is natriuretic peptides. The natriuretic peptide clearance receptor (NPRC) binds and degrades natriuretic peptides. As a result, NPRC inhibits natriuretic peptide-induced cGMP generation. To enhance cGMP generation in podocytes, we blocked natriuretic peptide clearance using the specific NPRC ligand ANP(4-23). We then studied the effects of NPRC blockade in both cultured podocytes and in a mouse transgenic (TG) model of focal segmental glomerulosclerosis (FSGS) created in our laboratory. In this model, a single dose of the podocyte toxin puromycin aminonucleoside (PAN) causes robust albuminuria in TG mice, but only mild disease in non-TG animals. We found that natriuretic peptides protected cultured podocytes from PAN-induced apoptosis, and that ANP(4-23) enhanced natriuretic peptide-induced cGMP generation in vivo. PAN-induced heavy proteinuria in vehicle-treated TG mice, and this increase in albuminuria was reduced by treatment with ANP(4-23). Treatment with ANP(4-23) also reduced the number of mice with glomerular injury and enhanced urinary cGMP excretion, but these differences were not statistically significant. Systolic BP was similar in vehicle and ANP(4-23)-treated mice. These data suggest that: 1. Pharmacologic blockade of NPRC may be useful for treating glomerular diseases such as FSGS, and 2. Treatment outcomes might be improved by optimizing NPRC blockade to inhibit natriuretic peptide clearance more effectively.
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Affiliation(s)
- Liming Wang
- Division of NephrologyDepartment of MedicineDuke University and Durham VA Medical CentersDurhamNorth CarolinaUSA
| | - Yuping Tang
- Division of NephrologyDepartment of MedicineDuke University and Durham VA Medical CentersDurhamNorth CarolinaUSA
| | - Anne F. Buckley
- Department of PathologyDuke University Medical CenterDurhamNorth CarolinaUSA
| | - Robert F. Spurney
- Division of NephrologyDepartment of MedicineDuke University and Durham VA Medical CentersDurhamNorth CarolinaUSA
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Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, Cook HT, Fervenza FC, Gibson KL, Glassock RJ, Jayne DR, Jha V, Liew A, Liu ZH, Mejía-Vilet JM, Nester CM, Radhakrishnan J, Rave EM, Reich HN, Ronco P, Sanders JSF, Sethi S, Suzuki Y, Tang SC, Tesar V, Vivarelli M, Wetzels JF, Floege J. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100:S1-S276. [PMID: 34556256 DOI: 10.1016/j.kint.2021.05.021] [Citation(s) in RCA: 1012] [Impact Index Per Article: 253.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022]
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Kawaguchi T, Imasawa T, Kadomura M, Kitamura H, Maruyama S, Ozeki T, Katafuchi R, Oka K, Isaka Y, Yokoyama H, Sugiyama H, Sato H. Focal segmental glomerulosclerosis histologic variants and renal outcomes based on nephrotic syndrome, immunosuppression, and proteinuria remission. Nephrol Dial Transplant 2021; 37:1679-1690. [PMID: 34499164 DOI: 10.1093/ndt/gfab267] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The associations of focal segmental glomerulosclerosis (FSGS) histologic variants with renal outcomes have rarely been investigated comprehensively by clinically relevant subgroups in this modern age. METHODS Data on 304 (173 nephrotic and 131 non-nephrotic) patients with biopsy-confirmed FSGS from 2010 to 2013 were analyzed using the Japanese nationwide renal biopsy registry. The primary outcome was a composite of a 30% decline in estimated glomerular filtration rate or progression to end stage kidney disease 5 years from the biopsy. We compared outcomes of FSGS variants according to the Columbia classification using survival analyses. Subgroup analyses were performed based on nephrotic syndrome (NS), immunosuppression, and proteinuria remission (PR, proteinuria <0.3 g/day) during follow-up. Additionally, associations of NS, immunosuppression, and PR with outcomes were examined for each variant. RESULTS The distribution of variants was 48% (n = 145) FSGS not otherwise specified (NOS), 19% (n = 57) tip, 15% (n = 47) perihilar, 13% (n = 40) cellular, and 5% (n = 15) collapsing. The outcome event occurred in 87 patients (29%). No significant differences in the outcome were found among the variants. Subgroup analyses yielded similar results. However, there was a trend toward improved outcome in patients with PR irrespective of variants (hazard ratio adjusted for histologic variant and potential confounders [adjusted HR]: 0.19 [95% confidence interval (CI), 0.10-0.34]). NS was marginally associated with better outcome compared with non-NS (adjusted HR: 0.50 [95% CI, 0.25-1.01]. CONCLUSIONS FSGS variants alone might not have significant impacts on the renal outcome after 5 years, while PR could be predictive of improved renal prognosis for any variant. Specific strategies and interventions to achieve PR for each variant should be implemented for better renal outcomes.
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Affiliation(s)
- Takehiko Kawaguchi
- Department of Nephrology, National Hospital Organization Chibahigashi National Hospital, Chiba, Japan
| | - Toshiyuki Imasawa
- Department of Nephrology, National Hospital Organization Chibahigashi National Hospital, Chiba, Japan
| | - Moritoshi Kadomura
- Department of Nephrology, National Hospital Organization Chibahigashi National Hospital, Chiba, Japan
| | - Hiroshi Kitamura
- Department of Pathology, National Hospital Organization Chibahigashi National Hospital, Chiba, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Takaya Ozeki
- Department of Nephrology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | | | - Kazumasa Oka
- Department of Pathology, Prefectural Nishinomiya Hospital, Hyogo, Japan
| | - Yoshitaka Isaka
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hitoshi Yokoyama
- Department of Nephrology, Kanazawa Medical University School of Medicine, Ishikawa, Japan
| | - Hitoshi Sugiyama
- Department of Human Resource Development of Dialysis Therapy for Kidney Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroshi Sato
- Department of Internal Medicine, JR Sendai Hospital, Miyagi, Japan
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De Vriese AS, Wetzels JF, Glassock RJ, Sethi S, Fervenza FC. Therapeutic trials in adult FSGS: lessons learned and the road forward. Nat Rev Nephrol 2021; 17:619-630. [PMID: 34017116 PMCID: PMC8136112 DOI: 10.1038/s41581-021-00427-1] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/09/2021] [Indexed: 02/03/2023]
Abstract
Focal segmental glomerulosclerosis (FSGS) is not a specific disease entity but a lesion that primarily targets the podocyte. In a broad sense, the causes of the lesion can be divided into those triggered by a presumed circulating permeability factor, those that occur secondary to a process that might originate outside the kidneys, those caused by a genetic mutation in a podocyte or glomerular basement membrane protein, and those that arise through an as yet unidentifiable process, seemingly unrelated to a circulating permeability factor. A careful attempt to correctly stratify patients with FSGS based on their clinical presentation and pathological findings on kidney biopsy is essential for sound treatment decisions in individual patients. However, it is also essential for the rational design of therapeutic trials in FSGS. Greater recognition of the pathophysiology underlying podocyte stress and damage in FSGS will increase the likelihood that the cause of an FSGS lesion is properly identified and enable stratification of patients in future interventional trials. Such efforts will facilitate the identification of effective therapeutic agents.
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Affiliation(s)
- An S De Vriese
- Division of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge, Brugge, Belgium
- Department of Internal Medicine, Ghent University, Ghent, Belgium
| | - Jack F Wetzels
- Department of Nephrology, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Richard J Glassock
- Department of Medicine, Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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Steroid resistant focal segmental glomerulosclerosis: effect of arterial hyalinosis on outcome: single center study. ROMANIAN JOURNAL OF INTERNAL MEDICINE = REVUE ROUMAINE DE MÉDECINE INTERNE 2021; 59:127-133. [PMID: 33565308 DOI: 10.2478/rjim-2020-0045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Indexed: 11/20/2022]
Abstract
Background. Few data with adequate evidence exists as regards the effect of Cyclosporine (CsA) and mycophenolate mofetil (MMF) on pathological prognostic parameters in patients with steroid resistant focal segmental glomerulosclerosis (FSGS). The purpose of the present study is to compare the effect of cyclosporin and mycophenolate mofetil in addition to steroids on functional and histopathologic renal parameters in patients with steroid resistant FSGS one year after treatment.Material and methods. Thirty-seven adults with primary FSGS patients resistant to steroid therapy consecutively randomized to treatment with either MMF or cyclosporine. Low dose prednisolone added to both groups. Glomerular filtration rate (GFR) and blood pressure (BP) were determined at all examinations and a second renal biopsy was taken 12 months after treatment with either of cyclosporin and mycophenolate mofetil.Results. GFR significantly increased in MMF group p < 0.01 after 6 months and unchanged after 12 months. On the other hand, GFR significantly decrease in CsA group p < 0.001 after 6 months and reduced more after 12 months p < 0.001 compared to base line levels. There was a significant difference of GFR between the 2 groups at 6 months p < 0.001. The extent of proteinuria decreased significantly in CsA group after 12 months p < 0.001. The extent of arteriolar hyalinosis increased significantly in CsA group (0.78 to 1.81 score, p < 0.001) but was unchanged in MMF group (0.93 to 0.96 score), whereas interstitial fibrosis increased to same level in both groups (grade 3).Conclusion. Conversion to MMF in those patients may be superior to CsA as regards GFR after 12 months after treatment in spite of the presence of greater level of protein excretion. The increased arteriolar hyalinosis during CsA treatment most likely results in higher BP compared to MMF treatment in patients with FSGS resistant to steroids.
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Moret L, Ganea A, Dao M, Hummel A, Knebelman B, Subra JF, Noble J, Mariat C, Jourde-Chiche N, Toure F, Garrouste C, Laurent C, Adeline L, Delmas Y, Cez A, Fritz O, Mousson C, Pouteau LM, Moranne O, Halimi JM, Audard V. Apheresis in Adult With Refractory Idiopathic Nephrotic Syndrome on Native Kidneys. Kidney Int Rep 2021; 6:2134-2143. [PMID: 34386662 PMCID: PMC8343786 DOI: 10.1016/j.ekir.2021.04.029] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 11/30/2022] Open
Abstract
Background Apheresis is the gold standard for idiopathic nephrotic syndrome (INS) relapse after transplantation, but it remains unknown whether such treatment is useful for adults with refractory INS on native kidneys. Methods This retrospective study included patients older than 16 years with biopsy-proven refractory (persistent nephrotic syndrome on corticosteroids plus at least 1 immunosuppressive drug) INS treated by apheresis and followed for at least 3 months. Results Between September 1997 and January 2020, 21 patients (focal segmental glomerulosclerosis: 12, minimal change nephrotic syndrome: 9, men: 67%, median age: 34 years) were identified. At last follow-up (12 months), 7 of 21 patients were in complete or partial remission. Remission was associated with older age (51 vs. 30 years, P = 0.05), lower proteinuria (3.9 vs. 7.3 g/d, P = 0.03), and lower estimated glomerular filtration rate (eGFR) (28.0 vs. 48.5 ml/min per 1.73 m2, P = 0.05) at apheresis. The need for dialysis before apheresis (odds ratio [OR] 22.0 [1.00–524], P = 0.026), age ≥50 years (OR: 22.6 [1.00–524], P = 0.006), a marked (>4.5 g/d) decrease in proteinuria (OR: 9.17 [1.15–73.2], P = 0.041), and a short (<12 months) time between diagnosis and apheresis (OR: 10.8 [1–117], P = 0.043) were significantly associated with remission. Three of 7 patients in remission who were initially on dialysis became dialysis-free; by contrast, none of the 14 patients without remission was initially on dialysis, but 5 of 14 had become dialysis-dependent (P = 0.01). Conclusion Apheresis may result in remission in adult patients with refractory INS, particularly in those at risk of renal failure, with limited sensitivity to medical treatments, if apheresis is initiated within a year of diagnosis.
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Affiliation(s)
- Léa Moret
- Service de Néphrologie-Hypertension, Dialyses, Transplantation Rénale, CHRU Tours, Tours, France
| | | | - Myriam Dao
- Service de Néphrologie, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Necker, Paris, France
| | - Aurélie Hummel
- Service de Néphrologie, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Necker, Paris, France
| | - Bertrand Knebelman
- Service de Néphrologie, Assistance Publique des Hôpitaux de Paris (AP-HP), Hôpital Necker, Paris, France
| | - Jean François Subra
- Service de Néphrologie-Dialyse-Transplantation, CHU d'Angers, Angers, France
| | - Johan Noble
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
| | - Christophe Mariat
- CHU Saint-Etienne, Hôpital Nord Avenue Albert Raimond, Saint Priest en Jarez, France
| | - Noémie Jourde-Chiche
- Aix-Marseille University, C2VN, INSERM, INRAE, AP-HM, Centre de Néphrologie et Transplantation Rénale, Marseille, France
| | - Fatouma Toure
- Service de Néphrologie-Dialyse-Transplantation Rénale, CHU Limoges, Limoges, France
| | - Cyril Garrouste
- Service de Néphrologie-Dialyse et Transplantation, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | | | - Lacraz Adeline
- Service Néphrologie Hémodialyse, CH de la côte Basque, Bayonne, France
| | - Yahsou Delmas
- Service de Néphrologie, Transplantation et Dialyse, CHU Bordeaux, Bordeaux, France
| | - Alexandre Cez
- Service de Néphrologie, AP-HP, Hôpital Tenon, Paris, France
| | - Olivier Fritz
- Service de Néphrologie, Centre Hospitalier de La Rochelle, La Rochelle, France
| | | | - Lise Marie Pouteau
- Service de Néphrologie et Hémodialyse, Centre Hospitalier de Laval, Laval, France
| | - Olivier Moranne
- Service de Néphrologie-Dialyses-Aphérèse, Hôpital Caremeau, CHU Nîmes, Nîmes, France
| | - Jean-Michel Halimi
- Service de Néphrologie-Hypertension, Dialyses, Transplantation Rénale, CHRU Tours, Tours, France.,EA4245, Université François-Rabelais, Tours, France.,INI-CRCT, Vandœuvre-lès-Nancy, France
| | - Vincent Audard
- Service de Néphrologie et Transplantation, Centre de Référence Maladie Rare « Syndrome Néphrotique Idiopathique », Fédération Hospitalo-Universitaire « Innovative Therapy for Immune Disorders », AP-HP, Hôpitaux Universitaires Henri Mondor, Créteil, France.,University of Paris Est Créteil, Institut National de la Santé et de la Recherche Médicale (INSERM) U955, Institut Mondor de Recherche Biomédicale (IMRB), Equipe 21, Créteil, France
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Cytoskeleton Rearrangements Modulate TRPC6 Channel Activity in Podocytes. Int J Mol Sci 2021; 22:ijms22094396. [PMID: 33922367 PMCID: PMC8122765 DOI: 10.3390/ijms22094396] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 04/16/2021] [Accepted: 04/20/2021] [Indexed: 12/15/2022] Open
Abstract
The actin cytoskeleton of podocytes plays a central role in the functioning of the filtration barrier in the kidney. Calcium entry into podocytes via TRPC6 (Transient Receptor Potential Canonical 6) channels leads to actin cytoskeleton rearrangement, thereby affecting the filtration barrier. We hypothesized that there is feedback from the cytoskeleton that modulates the activity of TRPC6 channels. Experiments using scanning ion-conductance microscopy demonstrated a change in migration properties in podocyte cell cultures treated with cytochalasin D, a pharmacological agent that disrupts the actin cytoskeleton. Cell-attached patch-clamp experiments revealed that cytochalasin D increases the activity of TRPC6 channels in CHO (Chinese Hamster Ovary) cells overexpressing the channel and in podocytes from freshly isolated glomeruli. Furthermore, it was previously reported that mutation in ACTN4, which encodes α-actinin-4, causes focal segmental glomerulosclerosis and solidifies the actin network in podocytes. Therefore, we tested whether α-actinin-4 regulates the activity of TRPC6 channels. We found that co-expression of mutant α-actinin-4 K255E with TRPC6 in CHO cells decreases TRPC6 channel activity. Therefore, our data demonstrate a direct interaction between the structure of the actin cytoskeleton and TRPC6 activity.
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Current Therapies in Nephrotic Syndrome: HDAC inhibitors, an Emerging Therapy for Kidney Diseases. CURRENT RESEARCH IN BIOTECHNOLOGY 2021. [DOI: 10.1016/j.crbiot.2021.05.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
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Podestà MA, Ponticelli C. Autoimmunity in Focal Segmental Glomerulosclerosis: A Long-Standing Yet Elusive Association. Front Med (Lausanne) 2020; 7:604961. [PMID: 33330569 PMCID: PMC7715033 DOI: 10.3389/fmed.2020.604961] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 10/26/2020] [Indexed: 01/17/2023] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a histological term that describes a pathologic renal entity affecting both adults and children, with a wide array of possible underlying etiologies. Podocyte damage with scarring, the hallmark of this condition, leads to altered permeability of the glomerular barrier, which may result in massive proteinuria and relentless renal function deterioration. A definite cause of focal segmental glomerulosclerosis can be confirmed in a minority of cases, while most forms have been traditionally labeled as primary or idiopathic. Despite this definition, increasing evidence indicates that primary forms are a heterogenous group rather than a single disease entity: several circulating factors that may affect glomerular permeability have been proposed as potential culprits, and both humoral and cellular immunity have been implicated in the pathogenesis of the disease. Consistently, immunosuppressive drugs are considered as the cornerstone of treatment for primary focal segmental glomerulosclerosis, but response to these agents and long-term outcomes are highly variable. In this review we provide a summary of historical and recent advances on the pathogenesis of primary focal segmental glomerulosclerosis, focusing on implications for its differential diagnosis and treatment.
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Forster BM, Nee R, Little DJ, Greasley PJ, Hughes JB, Gordon SM, Olson SW. Focal Segmental Glomerulosclerosis, Risk Factors for End Stage Kidney Disease, and Response to Immunosuppression. KIDNEY360 2020; 2:105-113. [PMID: 35368810 PMCID: PMC8785735 DOI: 10.34067/kid.0006172020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 11/30/2020] [Indexed: 02/04/2023]
Abstract
Background FSGS is a heterogeneic glomerular disease. Risk factors for kidney disease ESKD and the effect of immunosuppression treatment (IST) has varied in previously published cohorts. These cohorts were limited by relatively small case numbers, short follow-up, lack of racial/ethnic diversity, a mix of adult and pediatric patients, lack of renin-angiotensin-aldosterone system (RAAS) inhibition, or lack of subgroup analysis of IST. Methods We compared demographics, clinical characteristics, histopathology, and IST to long-term renal survival in a large, ethnically diverse, adult cohort of 338 patients with biopsy-proven FSGS with long-term follow-up in the era of RAAS inhibition using data from the US Department of Defense health care network. Results Multivariate analysis showed that nephrotic-range proteinuria (NRP), eGFR <60 ml/min per 1.73 m2, hypoalbuminemia, interstitial fibrosis and tubular atrophy, and interstitial inflammation at diagnosis and the absence of remission were all associated with worse long-term renal survival. IgM, C3, and a combination of IgM/C3 immunofluorescence staining were not associated with reduced renal survival. IST was not associated with improved renal survival in the whole cohort, or in a subgroup with NRP. However, IST was associated with better renal survival in a subgroup of patients with FSGS with both NRP and hypoalbuminemia and hypoalbuminemia alone. Conclusions Our study suggests that IST should be reserved for patients with FSGS and nephrotic syndrome. It also introduces interstitial inflammation as a potential risk factor for ESKD and does not support the proposed pathogenicity of IgM and complement activation.
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Affiliation(s)
- Benjamin M. Forster
- Walter Reed National Military Medical Center, Nephrology Department, Bethesda, Maryland
| | - Robert Nee
- Walter Reed National Military Medical Center, Nephrology Department, Bethesda, Maryland
| | - Dustin J. Little
- Walter Reed National Military Medical Center, Nephrology Department and Late Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland
| | - Peter J. Greasley
- Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - James B. Hughes
- Walter Reed National Military Medical Center, Nephrology Department, Bethesda, Maryland
| | - Sarah M. Gordon
- Tripler Army Medical Center, Nephrology Department, Honolulu, Hawaii
| | - Stephen W. Olson
- Walter Reed National Military Medical Center, Nephrology Department, Bethesda, Maryland
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Abstract
Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.
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50
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Usui T, Morito N, Shawki HH, Sato Y, Tsukaguchi H, Hamada M, Jeon H, Yadav MK, Kuno A, Tsunakawa Y, Okada R, Ojima T, Kanai M, Asano K, Imamura Y, Koshida R, Yoh K, Usui J, Yokoi H, Kasahara M, Yoshimura A, Muratani M, Kudo T, Oishi H, Yamagata K, Takahashi S. Transcription factor MafB in podocytes protects against the development of focal segmental glomerulosclerosis. Kidney Int 2020; 98:391-403. [DOI: 10.1016/j.kint.2020.02.038] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 02/21/2020] [Accepted: 02/28/2020] [Indexed: 12/31/2022]
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