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Tanimizu H, Sawa N, Sekine A, Oba Y, Yamanouchi M, Hasegawa E, Suwabe T, Hoshino J, Kinowaki K, Kono K, Ohashi K, Kanetsuna Y, Honda K, Joh K, Yamaguchi Y, Wada T, Ubara Y. Human immunodeficiency virus-associated nephropathy mainly due to cellular variant of focal segmental glomerulosclerosis. CEN Case Rep 2025; 14:345-350. [PMID: 40095283 DOI: 10.1007/s13730-025-00979-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 02/03/2025] [Indexed: 03/19/2025] Open
Abstract
A 45-year-old man with a low titer of hepatitis B virus (HBV) was diagnosed with nephrotic syndrome. A subsequent test for human immunodeficiency virus (HIV) was positive. Kidney biopsy revealed some signs of collapsing variant of focal segmental glomerulosclerosis (FSGS), but the predominant finding was a cellular variant of FSGS. Two years after receiving tenofovir, urine protein became negative, and the patient was finally diagnosed with HIV-associated nephropathy. Collapsing variant of FSGS is considered typical of HIV-related nephropathy, but the cellular variant of FSGS in this patient represents another type. The cause of many FSGSs is often never identified, making cause-based treatment difficult. This case demonstrates that identification of the cause of FSGS can lead to treatment of FSGS.
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Affiliation(s)
- Hikaru Tanimizu
- Nephrology Center, Toranomon Hospital, 2-2-2, Minato-City, ToranomonTokyo, 105-0001, Japan.
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan.
| | - Naoki Sawa
- Nephrology Center, Toranomon Hospital, 2-2-2, Minato-City, ToranomonTokyo, 105-0001, Japan
| | - Akinari Sekine
- Nephrology Center, Toranomon Hospital, 2-2-2, Minato-City, ToranomonTokyo, 105-0001, Japan
| | - Yuki Oba
- Nephrology Center, Toranomon Hospital, 2-2-2, Minato-City, ToranomonTokyo, 105-0001, Japan
| | - Masayuki Yamanouchi
- Nephrology Center, Toranomon Hospital, 2-2-2, Minato-City, ToranomonTokyo, 105-0001, Japan
| | - Eiko Hasegawa
- Nephrology Center, Toranomon Hospital, 2-2-2, Minato-City, ToranomonTokyo, 105-0001, Japan
| | - Tatsuya Suwabe
- Nephrology Center, Toranomon Hospital, 2-2-2, Minato-City, ToranomonTokyo, 105-0001, Japan
| | - Junichi Hoshino
- Nephrology Center, Toranomon Hospital, 2-2-2, Minato-City, ToranomonTokyo, 105-0001, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | | | - Kei Kono
- Department of Pathology, Toranomon Hospital, Tokyo, Japan
| | - Kenichi Ohashi
- Department of Pathology, Toranomon Hospital, Tokyo, Japan
- Department of Pathology, Hospital of Yokohama City University, Yokohama, Kanagawa, Japan
| | - Yukiko Kanetsuna
- Department of Pathology, International University of Health and Welfare, Narita, Japan
| | - Kazuho Honda
- Department of Anatomy, Showa University School of Medicine, Tokyo, Japan
| | - Kensuke Joh
- Department of Pathology, Jikei University, Minato, Japan
| | | | - Takehiko Wada
- Nephrology Center, Toranomon Hospital, 2-2-2, Minato-City, ToranomonTokyo, 105-0001, Japan
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Yoshifumi Ubara
- Nephrology Center, Toranomon Hospital, 2-2-2, Minato-City, ToranomonTokyo, 105-0001, Japan.
- Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan.
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Oshima Y, Sawa N, Yamanouchi M, Sekine A, Mizuno H, Ikuma D, Oba Y, Inoue N, Tanaka K, Hasegawa E, Suwabe T, Kono K, Kinowaki K, Ohashi K, Yamaguchi Y, Hoshino J, Ubara Y. Clinicopathological cohort study of kidney biopsy findings resulting in dialysis during long-term follow-up exceeding 30 years. Clin Exp Nephrol 2025:10.1007/s10157-025-02706-8. [PMID: 40434507 DOI: 10.1007/s10157-025-02706-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 05/19/2025] [Indexed: 05/29/2025]
Abstract
BACKGROUND Numerous kidney diseases progress to end-stage kidney disease (ESKD); however, a limited number of cohort studies have evaluated the underlying kidney diseases through kidney biopsy (KB). METHODS We retrospectively evaluated all patients who initiated dialysis at Toranomon Hospital, Japan, from 1985 to 2019, and whose underlying kidney disease had been diagnosed by KB. The data on histopathological diagnosis and various clinical characteristics were collected and analyzed for 357 patients. RESULTS The most prevalent underlying diseases, which constituted the primary endpoint of this study, were diabetic nephropathy (DN; n = 100, 28.0%), IgA nephropathy (IgAN; n = 99, 27.7%), and focal segmental glomerulosclerosis (n = 34, 9.5%). Benign nephrosclerosis (BNS; n = 1, 0.3%), that is, arteriosclerosis/arteriolosclerosis without distinct glomerulopathy, was rare. As the secondary endpoint, Cox regression analysis revealed that lower eGFR (p < 0.0001), higher proteinuria (p < 0.0001), older age (p = 0.005) and presence of DN (p = 0.008) were significant independent risk factors for early dialysis initiation. In the subgroup analysis, when comparing DN and IgAN, significantly earlier dialysis initiation was observed in DN than in IgAN by log-rank analysis (p < 0.0001), as well as after adjustment for baseline clinical characteristics using propensity score matching (n = 45 each) (p = 0.023). CONCLUSIONS We identified a list of kidney diseases that were at risk for ESKD at the time of KB through a long-term follow-up. DN and IgAN are the two primary causes of ESKD, whereas BNS is an infrequent direct cause of ESKD in patients requiring kidney biopsy.
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Affiliation(s)
- Yoichi Oshima
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan.
- Department of Nephrology, Tokyo Saiseikai Central Hospital, Tokyo, Japan.
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Kawasaki, Kanagawa, 213-8587, Japan.
| | - Naoki Sawa
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Kawasaki, Kanagawa, 213-8587, Japan
| | - Masayuki Yamanouchi
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Kawasaki, Kanagawa, 213-8587, Japan
| | - Akinari Sekine
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Kawasaki, Kanagawa, 213-8587, Japan
| | - Hiroki Mizuno
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Kawasaki, Kanagawa, 213-8587, Japan
| | - Daisuke Ikuma
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Kawasaki, Kanagawa, 213-8587, Japan
| | - Yuki Oba
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Kawasaki, Kanagawa, 213-8587, Japan
| | - Noriko Inoue
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Kiho Tanaka
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Eiko Hasegawa
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
| | - Tatsuya Suwabe
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Kawasaki, Kanagawa, 213-8587, Japan
| | - Kei Kono
- Department of Pathology, Toranomon Hospital, Tokyo, Japan
| | | | - Kenichi Ohashi
- Department of Pathology, Toranomon Hospital, Tokyo, Japan
- Department of Human Pathology, Institute of Science Tokyo, Tokyo, Japan
| | | | - Junichi Hoshino
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Yoshifumi Ubara
- Nephrology Center and Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan
- Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Kawasaki, Kanagawa, 213-8587, Japan
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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 2025; 486:1049-1059. [PMID: 39271482 PMCID: PMC12095447 DOI: 10.1007/s00428-024-03919-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 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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Salmon E, Trachtman H. Emerging pharmacotherapies for the treatment of childhood nephrotic syndrome. Expert Opin Pharmacother 2025; 26:879-885. [PMID: 40232128 DOI: 10.1080/14656566.2025.2493895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/09/2025] [Accepted: 04/11/2025] [Indexed: 04/16/2025]
Abstract
INTRODUCTION Childhood nephrotic syndrome (NS) is a relatively rare condition but an important cause of morbidity. It is classified based on histopathology and response to corticosteroid therapy. AREAS COVERED Children with steroid-sensitive disease have a favorable long-term prognosis with maintenance of normal kidney function. However, nearly half of these patients have persistent disease activity requiring chronic corticosteroid therapy or exposure to second-line immunosuppressive agents. The identification of anti-nephrin antibodies in many patients with steroid-sensitive disease suggests immunotherapy to reduce pathogenic antibody formation may represent a qualitative advance in treatment. Children with steroid-resistant disease are likely to have focal segmental glomerulosclerosis (FSGS). There are no approved treatments for this condition. FSGS is a heterogeneous entity, and improvements in care will likely depend on molecular classification of subtypes based on the underlying disease mechanism. This approach will enable selection of treatments that match the cause of NS in each child for precision medicine therapy. EXPERT OPINION Children with NS today benefit from therapeutic options not previously available, but clinical decisions still rely on steroid responsiveness at disease onset. Continued advancement in treating NS requires collaboration between basic scientists and nephrologists and the organization of a clinical trial framework to evaluate novel therapies.
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Affiliation(s)
- Eloise Salmon
- Department of Pediatrics, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA
| | - Howard Trachtman
- Department of Pediatrics, Division of Nephrology, University of Michigan, Ann Arbor, MI, USA
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5
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Shu Y, Huang J, Jiang L, Zhang YM, Wang F, Wang X, Meng LQ, Cheng XY, Liu G, Wang SX, Zhao MH, Ronco P, Cui Z. Anti-nephrin antibodies in adult Chinese patients with minimal change disease and primary focal segmental glomerulosclerosis. Kidney Int 2025:S0085-2538(25)00257-1. [PMID: 40147632 DOI: 10.1016/j.kint.2025.02.028] [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: 08/21/2024] [Revised: 02/02/2025] [Accepted: 02/25/2025] [Indexed: 03/29/2025]
Abstract
Anti-nephrin autoantibodies have been discovered in patients with minimal change disease (MCD) and primary focal segmental glomerulosclerosis (FSGS), especially in those with active nephrotic syndrome. Here, we investigated the prevalence and clinical significance of anti-nephrin antibodies in 596 adult Chinese patients (436 with MCD and 160 with primary FSGS) diagnosed by kidney biopsy. Anti-nephrin IgG and IgM were detected using ELISA, with validation through antigen-inhibition ELISA and Western blotting. Clinical data at biopsy and during the follow-up period were analyzed. Anti-nephrin antibodies were detected in 43% of all patients, with 30% testing positive for anti-nephrin IgG, 26% for anti-nephrin IgM, and 13.1% for both antibodies. The prevalence of anti-nephrin antibodies was higher in patients with nephrotic-range proteinuria who were not receiving steroids or immunosuppressants (51.1%). Patients with positive anti-nephrin antibodies exhibited more severe nephrotic syndrome, higher rates of relapse, and a shorter relapse-free period compared to those negative for these antibodies. Clinical features were similar between those with IgG and IgM. Notably, patients with both anti-nephrin IgG and IgM had the most severe proteinuria and the highest relapse frequency, suggesting a dose-dependent effect. Longitudinal analysis revealed that anti-nephrin antibodies significantly decreased during clinical remission, while they reappeared preceding proteinuria relapse. Our study shows that anti-nephrin antibodies, including IgG and IgM, are detectable in adult patients with MCD and primary FSGS and are associated with active nephrotic syndrome and frequent relapse. These antibodies may serve as valuable biomarkers and potential therapeutic targets.
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Affiliation(s)
- 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, Beijing, 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, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Lei Jiang
- 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, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Yi-Miao Zhang
- 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, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Fang 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, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Xin 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, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Li-Qiang Meng
- 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, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Xu-Yang Cheng
- 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, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Gang Liu
- 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, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Su-Xia Wang
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, 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, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Pierre Ronco
- Sorbonne Université, and Institut National de la Santé et de la Recherche Médicale (Inserm), Unité Mixte de Recherche S1155, Paris, France; Department of Nephrology, Centre Hospitalier du Mans, Le Mans, France
| | - 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, Beijing, China; Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China.
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Ubara Y, Sawa N, Yamanouchi M, Kono K, Ohashi K. New interpretation of diabetic nephropathy or diabetic kidney disease from kidney biopsy: review article. Clin Exp Nephrol 2025:10.1007/s10157-025-02661-4. [PMID: 40126730 DOI: 10.1007/s10157-025-02661-4] [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: 12/24/2024] [Accepted: 03/07/2025] [Indexed: 03/26/2025]
Abstract
Many nephrologists considered that renal involvement in diabetes patients was seen as nodular glomerulosclerosis (i.e., Kimmelstiel-Wilson lesions). However, they diagnosed diabetic nephropathy or diabetic kidney disease (DKD) from clinical information on diabetes history, and reports of evaluation by kidney biopsy were scarce. Since the publication of the Tervaert classification of diabetic nephropathy in 2010, reports of kidney biopsy in these patients have increased. Analysis of biopsy specimens revealed not only the Tervaert classification (class I to IV) based on glomerular lesions, but also various other pathologies. Besides nodular lesions, findings included paratubular basement membrane insudative lesions (PTBMILs), polar vasculosis, and nephropathy associated with novel drugs (sodium-glucose transport protein 2 inhibitors and dipeptidyl peptidase-4 inhibitors). PTBMILs are unique to diabetic nephropathy. In patients with continuous hyperglycemia and excessive salt intake, elevated blood osmolality (calculated by serum Na × 2 + serum glucose/18 + serum urea nitrogen/2.8) leads to thirst and excessive drinking, which results in fluid overload and generalized edema. The increase in circulating blood volume is thought to induce PTBMILs because of the influx of serum components into the endothelium of glomerular vessels. This case series review presents diverse kidney biopsy findings in patients with diabetic nephropathy or diabetic kidney disease as well as the pathogenesis.
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Affiliation(s)
- Yoshifumi Ubara
- Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, Japan.
| | - Naoki Sawa
- Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, Japan
| | - Masayuki Yamanouchi
- Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minato, Tokyo, Japan
| | - Kei Kono
- Department of Pathology, Toranomon Hospital, Minato, Tokyo, Japan
| | - Kenichi Ohashi
- Department of Pathology, Toranomon Hospital, Minato, Tokyo, Japan
- Department of Human Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo City, Tokyo, Japan
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7
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Uro-Coste C, Lambert C, Audard V, Couzi L, Caillard S, Büchler M, Del Bello A, Malvezzi P, Pernin V, Colosio C, Mesnard L, Bertrand D, Martinez F, Ducloux D, Poulain C, Thierry A, Danthu C, Greze C, Lanaret C, Moal V, Hertig A, Dantal J, Legendre C, Chatelet V, Sicard A, Gosset C, Maillard N, Duveau A, Petit C, Kamar N, Heng AE, Anglicheau D, Garrouste C. Prophylactic treatment of FSGS recurrence in patients who relapsed on a previous kidney graft. Nephrol Dial Transplant 2025; 40:475-483. [PMID: 38794882 PMCID: PMC11879060 DOI: 10.1093/ndt/gfae108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation and is classically associated with a significant decrease in graft survival. A major risk factor is a prior history of FSGS recurrence on a previous graft. This analysis reports the impact of a prophylactic treatment of FSGS recurrence in very high-risk patients who experienced a recurrence on a previous graft. METHODS We performed a retrospective multicentre observational study in 25 French transplantation centres. The inclusion criteria were patients aged more than 18 years who had undergone kidney transplant between 31 December 2004 and 31 December 2020, and who had a history of FSGS recurrence on a previous graft. RESULTS We identified 66 patients: 40 received prophylactic treatment (PT+), including intravenous cyclosporine and/or rituximab and/or plasmapheresis, and 26 did not receive any prophylactic treatment (PT-). The time to progression to end-stage kidney disease was similar between groups. The PT+ group was younger at FSGS diagnosis and at the time of kidney retransplantation and lost their previous graft faster. The overall recurrence rate was 72.7% (76.9% in the PT- group and 70.0% in the PT+ group, P = .54). At least partial remission was achieved in 87.5% of patients. The 5-year graft survival was 67.7% [95% confidence interval (CI) 53.4%-78.4%]: 65.1% (95% CI 48.7%-77.4%) in patients with FSGS recurrence vs 77.3% (95% CI 43.8%-92.3%) in patients without recurrence (P = .48). CONCLUSION Our study suggests that prophylactic treatment should not be used routinely in patients receiving a second transplantation after recurrence of FSGS on a previous graft. The recurrence rate is high regardless of the use of prophylactic treatment. However, the 5-year graft survival remains satisfactory.
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Affiliation(s)
| | - Céline Lambert
- Unité de Biostatistiques, DRCI, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - Vincent Audard
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation Centre de Référence Maladie Rare « Syndrome Néphrotique Idiopathique », Hôpitaux Universitaires Henri-Mondor, Univ Paris Est Créteil, INSERM, IMRB, Créteil, France
| | - Lionel Couzi
- Service de Néphrologie, Transplantation, Dialyse et Aphérèses, CHU de Bordeaux, Bordeaux, France
| | - Sophie Caillard
- Service de Néphrologie, University Hospital, Strasbourg, France
| | - Matthias Büchler
- Service de Néphrologie et Immunologie Clinique, CHRU de Tours, Tours, France
| | - Arnaud Del Bello
- Département de Néphrologie et Transplantation d'Organes, CHU Toulouse, INSERM U1043, IFR–BMT, Université Paul Sabatier, Toulouse, France
| | - Paolo Malvezzi
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
| | - Vincent Pernin
- Service de Néphrologie, Dialyse et Transplantation, Hôpital Lapeyronie, CHU Montpellier, Montpellier, France
| | | | - Laurent Mesnard
- Assistance Publique – Hôpitaux de Paris, Soins Intensifs Néphrologiques et Rein Aigu, APHP Sorbonne Université, Hôpital Tenon, Paris, France
| | | | - Frank Martinez
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Didier Ducloux
- Service de Néphrologie, Dialyse et Transplantation, CHU Besançon, Besançon, France
| | - Coralie Poulain
- Service de Néphrologie-Médecine Interne-Dialyse-Transplantation, CHU d'Amiens, Amiens, France
| | - Antoine Thierry
- Service de Néphrologie-Hémodialyse-Transplantation Rénale, CHU de Poitiers, Poitiers, France
| | - Clément Danthu
- Service de Néphrologie, Dialyse et Transplantation, CHU Limoges, Limoges, France
| | - Clarisse Greze
- Service de Néphrologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | | | - Valérie Moal
- Aix Marseille Université, Assistance Publique Hôpitaux de Marseille, Hôpital Conception, Centre de Néphrologie et Transplantation Rénale, Marseille, France
| | | | - Jacques Dantal
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie Clinique, CHU Nantes, Nantes, France
| | - Christophe Legendre
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Valérie Chatelet
- Centre Universitaire des Maladies Rénales, Centre Hospitalier Universitaire de Caen, Caen, France
| | - Antoine Sicard
- Service de Néphrologie, Dialyse et Transplantation, CHU Nice, Nice, France
| | - Clément Gosset
- Service de Néphrologie, Dialyse et Transplantation, CHU Nice, Nice, France
| | - Nicolas Maillard
- Service de Néphrologie et Transplantation, CHU Saint-Etienne, Saint-Etienne, France
| | - Agnès Duveau
- Service de Néphrologie, CHU Angers, Angers, France
| | - Clémence Petit
- Institut de Transplantation Urologie Néphrologie (ITUN), Service de Néphrologie et Immunologie Clinique, CHU Nantes, Nantes, France
| | - Nassim Kamar
- Département de Néphrologie et Transplantation d'Organes, CHU Toulouse, INSERM U1043, IFR–BMT, Université Paul Sabatier, Toulouse, France
| | | | - Dany Anglicheau
- Assistance Publique des Hôpitaux de Paris, Service de Néphrologie et Transplantation, Hôpital Universitaire Necker-Enfants Malades, Université de Paris, Paris, France
| | - Cyril Garrouste
- Service de Néphrologie, CHU Clermont-Ferrand, Clermont-Ferrand, France
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8
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Bigatti C, Chiarenza DS, Angeletti A. To biopsy or not to biopsy a teenager with idiopathic nephrotic syndrome? Biopsy first. Pediatr Nephrol 2025; 40:571-578. [PMID: 39251432 PMCID: PMC11666677 DOI: 10.1007/s00467-024-06510-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 08/15/2024] [Accepted: 08/16/2024] [Indexed: 09/11/2024]
Abstract
Kidney biopsy plays a crucial role in the diagnosis and management of several glomerular diseases. While it is generally considered a routine and safe procedure in children, it should be conducted with the primary objective of addressing the following question: do the prognosis and treatments vary based on the findings of kidney biopsy? In children presenting with idiopathic nephrotic syndrome (INS), guidelines suggest to consider kidney biopsy for individuals older than 12 years, primarily due to the possible increased incidence of different glomerulonephritis compared to younger patients, who predominantly manifest with minimal change disease. However, these guidelines also advocate for uniform therapeutic strategies, typically steroids, irrespective of the age or histological findings. Whether the age of more than 12 years may be a recommendation for performing kidney biopsy at presentation of INS is debatable. Instead, kidney biopsy could be reserved for steroid-resistant cases. On the other hand, when kidney biopsy is performed in INS, particularly in focal segmental glomerulosclerosis, histology may reveal additional lesions, that are strongly associated with a poorer response to treatment and worse clinical outcomes. Therefore, current guidelines on treatments of nephrotic syndrome may appear overly restrictive, despite the relevant findings provided by kidney biopsy. Therefore, in the present manuscript, which is part of a pro-con debate on the management of nephrotic syndrome in adolescents, we emphasize the potential role of performing a kidney biopsy before initiating corticosteroid treatment.
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Affiliation(s)
- Carolina Bigatti
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Via Gaslini 5, 16147, Genoa, GE, Italy
| | - Decimo S Chiarenza
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Via Gaslini 5, 16147, Genoa, GE, Italy
| | - Andrea Angeletti
- Nephrology, Dialysis and Transplantation Unit, IRCCS Istituto Giannina Gaslini, Via Gaslini 5, 16147, Genoa, GE, Italy.
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9
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Figueiredo G, Yu L, Jorge LB, Woronik V, Dias CB. Nephrotic and Non-Nephrotic Focal Segmental Glomerulosclerosis: Clinical Characteristics, Etiology, and Columbia Classification. Diagnostics (Basel) 2025; 15:120. [PMID: 39857004 PMCID: PMC11763650 DOI: 10.3390/diagnostics15020120] [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: 12/05/2024] [Revised: 12/30/2024] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
Introduction: Focal segmental glomerulosclerosis (FSGS) is a pattern of kidney injury with diverse causes and pathogeneses, resulting in podocyte injury and depletion. It can be classified as primary, genetic, or secondary. Because FSGS classically has a worse prognosis in patients with nephrotic syndrome, most studies have focused on the treatment and evolution of these patients, resulting in a lack of data related to patients without nephrotic syndrome. The objective of this study was to establish the main etiologies, characteristics, and evolution of renal disease in FSGS patients with nephrotic and non-nephrotic proteinuria. Methods: This was a retrospective, single-center study that included 140 patients with a biopsy-confirmed diagnosis of FSGS in the 2009-2017 period. Patients were separated into those with and those without nephrotic syndrome at diagnosis, and these two groups were compared in terms of the clinical characteristics, histological profile, and outcome. Non-nephrotic patients with unfavorable progression were selected for ultrastructural analysis with electron microscopy. Results: During the study period, 32.9% of the patients with FSGS had non-nephrotic proteinuria at diagnosis. This group had a larger proportion of patients with hypertension and a not otherwise specified FSGS variant on histology. The proportion of patients with secondary forms of FSGS was comparable between the two groups, with HIV infection and systemic lupus erythematosus being predominant. Progression to renal replacement therapy occurred in 31.3% of the patients in the nephrotic group and in 26.8% of those in the non-nephrotic group, with no statistical difference between them. All of the non-nephrotic group patients who progressed to renal replacement therapy were analyzed by electron microscopy, the diagnosis of FSGS was confirmed, and there was the finding of high chronicity in these patients. Conclusions: Among patients with FSGS, those without nephrotic syndrome had a poor renal outcome at a frequency similar to that of those with nephrotic syndrome. Factors related to better renal survival were having had a complete response to treatment in the case of those with nephrotic syndrome and having achieved proteinuria values of less than 1.5 g/day in the case of those without nephrotic syndrome.
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Affiliation(s)
- Gabriel Figueiredo
- Nephrology Department, Hospital das Clínicas of São Paulo, São Paulo 05403-900, Brazil (L.Y.)
| | - Luis Yu
- Nephrology Department, Hospital das Clínicas of São Paulo, São Paulo 05403-900, Brazil (L.Y.)
| | - Lectícia Barbosa Jorge
- Nephrology Department, Hospital das Clínicas of São Paulo, São Paulo 05403-900, Brazil (L.Y.)
| | - Viktoria Woronik
- Laboratory of Renal Pathophysiology, Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo 05508-220, Brazil
| | - Cristiane Bitencourt Dias
- Laboratory of Renal Pathophysiology, Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo 05508-220, Brazil
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10
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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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11
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Bernardes TP, Paula TAF, Sales GTM, Calais PV, Foresto RD, Moura LA, Durão MDS, Pesquero JB, Kirsztajn GM. Collapsing glomerulopathy associated with parvovirus B19 and systemic lupus erythematosus in a patient with APOL1 high-risk variant for nephropathy. J Bras Nefrol 2025; 47:e20240104. [PMID: 39792859 PMCID: PMC11723606 DOI: 10.1590/2175-8239-jbn-2024-0104en] [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: 06/04/2024] [Accepted: 08/11/2024] [Indexed: 01/12/2025] Open
Abstract
Collapsing glomerulopathy (CG) has a severe course typically associated with viral infections, especially HIV and parvovirus B19, systemic lupus erythematosus (SLE), among other etiologies. A 35-year-old woman with recent use of a JAK inhibitor due to rheumatoid arthritis presented with a 2-week history of fever, cervical adenopathy, and facial erythema. After admission, anemia, hypoalbuminemia, proteinuria, and severe acute kidney injury were noted. SLE was diagnosed and parvovirus B19 DNA was detected in serum samples. Kidney biopsy showed CG without any typical features of lupus nephritis. The patient was treated with prednisone and presented marked improvement of anemia and kidney function after a few weeks. In this case, the patient with SLE presented CG possibly caused by parvovirus B19 infection associated with homozygous apolipoprotein 1 (APOL1) G1 genotype, which has been described as a determinant risk factor for this glomerulopathy. It is not clear whether SLE had a causal relationship with glomerular disease or was a concurrent cause. Treatment can be challenging in such a context, as no antiviral drug is efficient and immunosuppression has no discernable benefit, although steroid use was efficient in treating renal manifestations in this case.
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Affiliation(s)
| | | | | | - Patrícia Varela Calais
- Universidade Federal de São Paulo, Departamento de Biofísica, Centro de Pesquisa e Diagnóstico em Doenças Genéticas, São Paulo, SP, Brazil
| | | | - Luiz Antonio Moura
- Universidade Federal de São Paulo, Departamento de Medicina, São Paulo, SP, Brazil
- Fundação Oswaldo Ramos, Hospital do Rim, São Paulo, SP, Brazil
| | | | - João Bosco Pesquero
- Universidade Federal de São Paulo, Departamento de Biofísica, Centro de Pesquisa e Diagnóstico em Doenças Genéticas, São Paulo, SP, Brazil
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12
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Munis MA, Chen Q, Hill TM, Zhuo M, Schachter AD, Bhandari SK, Hever A, Harrison TN, Fernandes AW, Sim JJ. Incidence and Proportion of Primary Focal Segmental Glomerulosclerosis (FSGS) among a Racially and Ethnically Diverse Adult Patient Population between 2010 and 2021. Clin J Am Soc Nephrol 2024; 20:01277230-990000000-00479. [PMID: 39392691 PMCID: PMC11835197 DOI: 10.2215/cjn.0000000590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 10/07/2024] [Indexed: 10/13/2024]
Abstract
Key Points Primary FSGS is a rare immune mediated glomerulopathy that accounted for 16.6% for all FSGS reported biopsies among a diverse patient population. From 2010 to 2021, the standardized incidence of primary FSGS was estimated at 1.7 cases per 100,000 patient-years. The highest incidence of primary FSGS was observed among Black (3.2) and Asian (2.7 cases per 100,000 patient-years) people. Background Focal segmental glomerulosclerosis (FSGS) refers to a pattern of glomerular injury but also includes primary FSGS which is considered as an immune-mediated glomerulopathy. We sought to determine the incidence of primary FSGS and proportion of patients with FSGS who have primary FSGS among a large diverse patient population in the United States. Methods A cross-sectional study (2010–2021) was performed within an integrated health system in patients (age 18 or older) with biopsy-proven FSGS. Among biopsies with FSGS as the first diagnosis on pathology report, chart reviews were performed to determine primary FSGS, defined as podocyte foot process effacement ≥80% on electron microscopy. The proportion of patients with primary FSGS and annual incidence rate (IR) (per 100,000 patient-years) were calculated. Standardized IR were determined by age, sex, and race and ethnicity based on US population structure of the 5-year (2018–2022) American Community Survey estimates. Results We identified 3838 patients with FSGS reported on biopsy. Among 1502 with FSGS as the principal diagnosis, 637 met criteria for primary FSGS (mean [SD] age 55.5 years [17.9], 56.5% male, 35.6% Hispanic, 28.7% White, 17.9% Asian/Pacific Islander, and 16.0% Black). The mean standardized IR (confidence interval) of primary FSGS was 1.7 (0.9 to 2.5) per 100,000 patient-years during the study period. The standardized annual IR ranged from 1.3 to 2.4 per 100,000 patient-years. IR (per 100,000 patient-years) were highest among Black (3.2), Asian (2.7), and Pacific Islander (2.8) patients. Conclusions Primary FSGS accounted for 16.6% of biopsy-proven FSGS. Primary FSGS is a likely a rare disease with incidence highest among Black, Asian, and Pacific Islander people. More precise identification of primary FSGS may facilitate work to improve understanding of this glomerulopathy and improve kidney outcomes.
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Affiliation(s)
- Mercedes A. Munis
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
| | - Qiaoling Chen
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
| | - T. Matthew Hill
- Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey
| | - Min Zhuo
- Visterra Inc., Waltham, Massachusetts
| | | | - Simran K. Bhandari
- Department of Internal Medicine, Downey Medical Center, Downey, California
| | - Aviv Hever
- Department of Pathology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California
| | - Teresa N. Harrison
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
| | - Ancilla W. Fernandes
- Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey
| | - John J. Sim
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California
- Division of Nephrology and Hypertension, Kaiser Permanente Los Angeles Medical Center, Los Angeles, California
- Department of Clinical Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California
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13
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Yeboah EK, Yang Y, Nnaji O, Roche-Recinos A, Saggi S. Granulomatous Tubulointerstitial Nephritis as a Rare Cause of Allograft Failure: A Case Report. Cureus 2024; 16:e76353. [PMID: 39866980 PMCID: PMC11758257 DOI: 10.7759/cureus.76353] [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: 12/24/2024] [Indexed: 01/28/2025] Open
Abstract
Although granulomatous interstitial nephritis (GIN) is a rare histological finding in kidney transplants, the joint occurrence of GIN and focal segmental glomerulosclerosis (FSGS) has not, to our knowledge, been reported in the literature. We report a case of GIN and de novo FSGS in kidney transplant recipients leading to allograft failure. A 69-year-old male with a history of end-stage renal disease (ESRD) of unknown etiology, as well as liver failure from hepatitis B and C co-infection, initially had a living unrelated kidney transplant (LURT) in 2007 and subsequently received both liver and kidney transplants (SLKTs) in 2017. His second post-transplant course in 2017 was complicated by antibody-mediated rejection, recurrent urinary tract infections, and an episode of cell-mediated rejection, which was treated with both corticosteroids and thyroglobulin. In 2023, his serum creatinine remained stable, ranging from 2.2 to 2.9 mg/dL, with maintenance immunosuppression of mycophenolate mofetil (750 mg twice a day), tacrolimus (4 mg twice a day; target of 5-7 ng/mL), and prednisone (5 mg daily). In February 2024, his serum creatinine increased to 4.3 mg/dL, with nephrotic-range proteinuria (urine protein-to-creatinine ratio of 6000 mg/g) and urinalysis showing pyuria (white blood cell count of 49), but no hematuria. All infectious work-ups, including urine culture, blood culture, QuantiFERON-TB Gold, and sputum Mycobacterium tuberculosis polymerase chain reaction (MTB-PCR) (×3), were negative. An allograft biopsy showed acute granulomatous tubulo-interstitial nephritis, along with de novo collapsing FSGS and recurrent diabetic nephropathy. There was no evidence of active T-cell-mediated, vascular, or antibody-mediated rejection (negative C4d). The kidney biopsy for in-tissue MTB-PCR testing was negative. To the best of our knowledge, our patient is the first case of idiopathic GIN with non-necrotizing granulomata, along with de novo collapsing FSGS, leading to allograft failure.
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Affiliation(s)
- Eugene K Yeboah
- Internal Medicine, State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, USA
| | - Yihe Yang
- Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, USA
| | - Okwudili Nnaji
- Nephrology, State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, USA
| | - Andrea Roche-Recinos
- Transplant Nephrology, State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, USA
| | - Subodh Saggi
- Nephrology, State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, USA
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14
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Priyanka K, Deepthi B, Krishnasamy S, Ganesh RN, Sravani M, Krishnamurthy S. Kidney outcomes in children with primary focal segmental glomerulosclerosis from a low- and middle- income country. Pediatr Nephrol 2024; 39:3485-3495. [PMID: 38652137 DOI: 10.1007/s00467-024-06382-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 04/10/2024] [Accepted: 04/11/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Limited data exists regarding the clinical course and outcomes of children with primary focal segmental glomerulosclerosis (FSGS) from low- and middle- income countries. METHODS Children aged 1-18 years with biopsy-proven primary FSGS followed from January 2010-June 2023 in a tertiary-care center were enrolled and their clinical profile, histological characteristics, kidney outcomes, and predictors of adverse outcomes were determined. RESULTS Over 13 years, 73 (54.8% boys) children with median (IQR) age at FSGS diagnosis 6.7 (3,10) years were recruited and followed up for median 4 (2.5,8) years. FSGS-not otherwise specified (NOS) was the most common histological subtype, in 64 (87.6%) children, followed by collapsing variant in 5 (6.8%) children. At last follow-up, 43 (58.9%), 2 (2.7%) and 28 (38.3%) children were in complete remission (CR), partial remission (PR), and no remission (NR) respectively. Calcineurin inhibitors led to CR or PR in 39 (62%) children. Overall, 21 (28.7%) children progressed to chronic kidney disease (CKD) stage 2-5 (19 from NR vs. 2 from PR group; p = 0.03); with 41% of those NR at 12 months progressing to CKD 4-5 by last follow-up. On multivariable analysis, collapsing variant [adjusted HR 2.5 (95%CI 1.5, 4.17), p = 0.001] and segmental sclerosis > 25% [aHR 9.9 (95%CI 2.2, 45.2), p = 0.003] predicted kidney disease progression. CONCLUSIONS In children with FSGS, response to immunosuppression predicts kidney survival as evidenced by nil to lower progression to CKD 2-5 by median follow-up of 4 (2.5,8) years in children with CR and PR, compared to those with no remission at 12 months from diagnosis. Segmental sclerosis > 25% and collapsing variant predicted progression to advanced CKD.
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Affiliation(s)
- Kolluri Priyanka
- Pediatric Nephrology Services, Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India
| | - Bobbity Deepthi
- Pediatric Nephrology Services, Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India.
| | - Sudarsan Krishnasamy
- Pediatric Nephrology Services, Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India
| | - Rajesh Nachiappa Ganesh
- Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India
| | - Madhileti Sravani
- Pediatric Nephrology Services, Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India
| | - Sriram Krishnamurthy
- Pediatric Nephrology Services, Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India
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15
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Cantarelli C, Campbell KN, Cravedi P. Parietal epithelial cells in glomerulosclerosis: a new piece in the puzzle? J Nephrol 2024; 37:2057-2058. [PMID: 39354297 DOI: 10.1007/s40620-024-02100-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 09/01/2024] [Indexed: 10/03/2024]
Affiliation(s)
- Chiara Cantarelli
- UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
| | - Kirk N Campbell
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1 Levy Place, New York, NY, 10029, USA
| | - Paolo Cravedi
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1 Levy Place, New York, NY, 10029, USA.
- Department of Medicine, Translational Transplant Research Center (TTRC), Icahn School of Medicine at Mount Sinai, 1 Levy Place, New York, NY, USA.
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16
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Hejazian SM, Rahbar Saadat Y, Hosseiniyan Khatibi SM, Farnood F, Farzamikia N, Hejazian SS, Batoumchi S, Shoja MM, Zununi Vahed S, Ardalan M. Circular RNAs as novel biomarkers in glomerular diseases. Arch Physiol Biochem 2024; 130:568-580. [PMID: 37194131 DOI: 10.1080/13813455.2023.2212328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 05/03/2023] [Accepted: 05/03/2023] [Indexed: 05/18/2023]
Abstract
Circular RNAs (circRNAs) regulate gene expression and biological procedures by controlling target genes or downstream pathways by sponging their related miRNA (s). Three types of circRNAs have been identified; exonic circRNAs (ecircRNAs), intronic RNAs (ciRNAs), and exon-intron circRNAs (ElciRNAs). It is clarified that altered levels of circRNAs have dynamic pathological and physiological functions in kidney diseases. Evidence suggests that circRNAs can be considered novel diagnostic biomarkers and therapeutic targets for renal diseases. Glomerulonephritis (GN) is a general term used to refer to a wide range of glomerular diseases. GN is an important cause of chronic kidney diseases. Here, we review the biogenesis of circRNAs, and their molecular and physiological functions in the kidney. Moreover, the dysregulated expression of circRNAs and their biological functions are discussed in primary and secondary glomerulonephritis. Moreover, diagnostic and therapeutic values of circRNAs in distinguishing or treating different types of GN are highlighted.
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Affiliation(s)
| | | | | | - Farahnoosh Farnood
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Negin Farzamikia
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyyed Sina Hejazian
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sepideh Batoumchi
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammadali M Shoja
- College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA
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17
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Sohal A, Singh C, Bhalla A, Kalsi H, Roytman M. Renal Manifestations of Chronic Hepatitis C: A Review. J Clin Med 2024; 13:5536. [PMID: 39337023 PMCID: PMC11433393 DOI: 10.3390/jcm13185536] [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: 08/31/2024] [Revised: 09/13/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Hepatitis C virus (HCV) has emerged as a major global health concern and, if left untreated, can lead to significant liver damage, including cirrhosis, decompensated liver disease, and hepatocellular carcinoma (HCC). Approximately 40% of patients with HCV infection experience extrahepatic manifestations, including renal involvement. HCV-related renal disease is of significant importance among patients with chronic kidney disease (CKD), leading to higher morbidity and mortality. The renal damage due to HCV infection primarily results from cryoglobulinemia and glomerulonephritis, with conditions such as membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy (MN) being most prevalent. Despite advancements in treatment, including the use of directly acting antiviral agents (DAAs), renal complications remain a significant burden in untreated patients. HCV-positive patients on hemodialysis (HD) or those who have undergone kidney transplantation face increased mortality rates compared to their HCV-negative counterparts. Managing HCV infection before kidney transplantation is crucial to mitigate the risk of HCV-related renal complications. Conversely, kidney transplantation from HCV-infected donors is well established, as post-transplant treatment for HCV is safe and effective, potentially reducing mortality and morbidity for patients on transplant waiting lists. This review aims to provide a comprehensive analysis of the renal manifestations of HCV, emphasizing the importance of early diagnosis and treatment to improve patient outcomes.
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Affiliation(s)
- Aalam Sohal
- Division of Gastroenterology and Hepatology, Creighton University School of Medicine, Phoenix, AZ 2500, USA
| | - Carol Singh
- Department of Internal Medicine, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India
| | - Akshita Bhalla
- Department of Internal Medicine, Punjab Institute of Medical Sciences, Jalandhar 144006, Punjab, India
| | - Harsimran Kalsi
- Department of Internal Medicine, University of Central Florida College of Medicine, Orlando, FL 32827, USA
| | - Marina Roytman
- Division of Gastroenterology and Hepatology, University of California San Francisco, Fresno, CA 93701, USA
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18
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Hu X, Lin W, Luo Z, Zhong Y, Xiao X, Tang R. Frameshift Mutation in PAX2 Related to Focal Segmental Glomerular Sclerosis: A Case Report and Literature Review. Mol Genet Genomic Med 2024; 12:e70006. [PMID: 39235128 PMCID: PMC11375732 DOI: 10.1002/mgg3.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 08/14/2024] [Accepted: 08/20/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND Paired box gene 2 (PAX2) heterozygous mutations can cause renal coloboma syndrome, but its role in patients with focal segmental glomerular sclerosis (FSGS) has been rarely reported. METHODS Based on the clinical manifestations and renal pathological characteristics of the patient, as well as familial whole exome sequencing, the diagnosis of FSGS related to PAX2 mutation was confirmed. Treatment such as lowering urinary protein and blood pressure was given, and the patient was followed up and observed. RESULTS There is a familial heterozygous case presented with chronic kidney disease secondary to FSGS, which was related to PAX2 frameshift mutation due to the deletion of G at the position 76 (c.76delG). To our knowledge, this is the first report of PAX2 c.76delG variant related to adult-onset FSGS. CONCLUSION Here, we further expand the phenotypic spectrum of FSGS. Genetic screening especially PAX2 mutation is recommended in patients with adult-onset FSGS of unknown etiology.
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Affiliation(s)
- Xueling Hu
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Wei Lin
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Zengyuan Luo
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Yong Zhong
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Xiangcheng Xiao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Rong Tang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
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19
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Finn LS. Nephrotic Syndrome Throughout Childhood: Diagnosing Podocytopathies From the Womb to the Dorm. Pediatr Dev Pathol 2024; 27:426-458. [PMID: 38745407 DOI: 10.1177/10935266241242669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
The etiologies of podocyte dysfunction that lead to pediatric nephrotic syndrome (NS) are vast and vary with age at presentation. The discovery of numerous novel genetic podocytopathies and the evolution of diagnostic technologies has transformed the investigation of steroid-resistant NS while simultaneously promoting the replacement of traditional morphology-based disease classifications with a mechanistic approach. Podocytopathies associated with primary and secondary steroid-resistant NS manifest as diffuse mesangial sclerosis, minimal change disease, focal segmental glomerulosclerosis, and collapsing glomerulopathy. Molecular testing, once an ancillary option, has become a vital component of the clinical investigation and when paired with kidney biopsy findings, provides data that can optimize treatment and prognosis. This review focuses on the causes including selected monogenic defects, clinical phenotypes, histopathologic findings, and age-appropriate differential diagnoses of nephrotic syndrome in the pediatric population with an emphasis on podocytopathies.
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Affiliation(s)
- Laura S Finn
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at The University of Pennsylvania, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
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20
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Hou S, Yang B, Chen Q, Xu Y, Li H. Potential biomarkers of recurrent FSGS: a review. BMC Nephrol 2024; 25:258. [PMID: 39134955 PMCID: PMC11318291 DOI: 10.1186/s12882-024-03695-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 08/05/2024] [Indexed: 08/16/2024] Open
Abstract
Focal segmental glomerulosclerosis (FSGS), a clinicopathological condition characterized by nephrotic-range proteinuria, has a high risk of progression to end-stage renal disease (ESRD). Meanwhile, the recurrence of FSGS after renal transplantation is one of the main causes of graft loss. The diagnosis of recurrent FSGS is mainly based on renal puncture biopsy transplants, an approach not widely consented by patients with early mild disease. Therefore, there is an urgent need to find definitive diagnostic markers that can act as a target for early diagnosis and intervention in the treatment of patients. In this review, we summarize the domestic and international studies on the pathophysiology, pathogenesis and earliest screening methods of FSGS and describe the functions and roles of specific circulating factors in the progression of early FSGS, in order to provide a new theoretical basis for early diagnosis of FSGS recurrence, as well as aid the exploration of therapeutic targets.
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Affiliation(s)
- Shuang Hou
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China
| | - Bo Yang
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China
| | - Qian Chen
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China
| | - Yuan Xu
- Department of Organ Transplantation, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China.
| | - Haiyang Li
- Hepatological surgery department, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550000, China.
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21
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Filippone EJ, Gulati R, Farber JL. Contemporary review of IgA nephropathy. Front Immunol 2024; 15:1436923. [PMID: 39188719 PMCID: PMC11345586 DOI: 10.3389/fimmu.2024.1436923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/02/2024] [Indexed: 08/28/2024] Open
Abstract
IgA nephropathy (IgAN) is considered the most common primary glomerulonephritis worldwide with a predilection for Asian-Pacific populations and relative rarity in those of African descent. Perhaps 20%-50% of patients progress to kidney failure. The pathogenesis is incompletely understood. Mesangial deposition of immune complexes containing galactose-deficient IgA1 complexed with anti-glycan IgG or IgA antibodies results in mesangial cell activation and proliferation, inflammatory cell recruitment, complement activation, and podocyte damage. Diagnosis requires a biopsy interpreted by the Oxford criteria. Additional pathologic features include podocytopathy, thrombotic microangiopathy, and C4d staining. Biomarkers predicting adverse outcomes include proteinuria, reduced GFR, hypertension, and pathology. Acceptable surrogate endpoints for therapeutic trials include ongoing proteinuria and rate of eGFR decline. The significance of persisting hematuria remains uncertain. The mainstay of therapy is supportive, consisting of lifestyle modifications, renin-angiotensin inhibition (if hypertensive or proteinuric), sodium-glucose-transporter 2 inhibition (if GFR reduced or proteinuric), and endothelin-receptor antagonism (if proteinuric). Immunosuppression should be considered for those at high risk after maximal supportive care. Corticosteroids are controversial with the most positive results observed in Chinese. They carry a high risk of serious side effects. Similarly, mycophenolate may be most effective in Chinese. Other immunosuppressants are of uncertain benefit. Tonsillectomy appears efficacious in Japanese. Active areas of investigation include B-cell inhibition with agents targeting the survival factors BAFF and APRIL and complement inhibition with agents targeting the alternate pathway (Factors B and D), the lectin pathway (MASP-2), and the common pathway (C3 and C5). Hopefully soon, the who and the how of immunosuppression will be clarified, and kidney failure can be forestalled.
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Affiliation(s)
- Edward J. Filippone
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - Rakesh Gulati
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
| | - John L. Farber
- Department of Pathology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
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22
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Fisher M, Ross M, DiFranza L, Reidy K. An Update on Viral Infection-Associated Collapsing Glomerulopathy. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:317-325. [PMID: 39084757 PMCID: PMC11296492 DOI: 10.1053/j.akdh.2023.12.007] [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: 07/15/2023] [Revised: 11/14/2023] [Accepted: 12/14/2023] [Indexed: 08/02/2024]
Abstract
The COVID-19 era has been a reminder to clinicians around the world of the important role that viral infections play in promoting glomerular disease. Several viral infections including human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus 2, Epstein-Barr virus, cytomegalovirus, and parvovirus B19 can cause podocyte injury and present with a collapsing glomerulopathy (CG) variant of focal segmental glomerulosclerosis or minimal change disease. CG associated with COVID-19 has been termed COVID-19-associated nephropathy due to its striking resemblance to HIV-associated nephropathy. Host susceptibility is a major determinant of viral infection-associated CG, and the presence of two APOL1 risk variants explains most of the racial predilection to viral-associated CG observed in individuals of African ancestry. Interactions between APOL1 risk variants, viral genes, and the systemic inflammatory response to viral infection all contribute to kidney injury. This review will summarize our current knowledge of viral infection-associated CG, focusing primarily on the clinical presentation, histological features, mechanisms, and disease course of HIV-associated nephropathy and COVID-19-associated nephropathy.
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Affiliation(s)
- Molly Fisher
- Division of Nephrology, Albert Einstein College of Medicine, Montefiore Health System, Bronx, NY.
| | - Michael Ross
- Division of Nephrology, Albert Einstein College of Medicine, Montefiore Health System, Bronx, NY; Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY
| | - Lanny DiFranza
- Department of Pathology, Albert Einstein College of Medicine, Montefiore Health System, Bronx, NY
| | - Kimberly Reidy
- Division of Pediatric Nephrology, The Children's Hospital at Montefiore/Albert Einstein College of Medicine, Bronx, NY
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23
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Suresh V, Stillman IE, Campbell KN, Meliambro K. Focal Segmental Glomerulosclerosis. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:275-289. [PMID: 39084753 DOI: 10.1053/j.akdh.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 03/27/2024] [Accepted: 03/29/2024] [Indexed: 08/02/2024]
Abstract
Focal segmental glomerular sclerosis (FSGS) is a histological lesion characterized by sclerosis in sections (segmental) of some glomeruli (focal) in association with podocyte injury. Historically, FSGS has often been characterized as a disease, but it is a heterogeneous entity based on etiology, clinical course, and therapeutic approach. A unifying feature is podocyte injury and loss, which can be primary or the result of secondary maladaptive responses to glomerular stressors. FSGS has been demonstrated over time to carry a large health burden and remains a leading glomerular cause of ESRD globally. Recent clinical practice guidelines highlight the unmet scientific need for better understanding of disease pathogenesis, particularly for immunologic etiologies, as well as more targeted therapeutic drug development. In this review, we will discuss the current FSGS classification scheme, pathophysiologic mechanisms of injury, and treatment guidelines, along with emerging and investigational therapeutics.
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Affiliation(s)
- Varsha Suresh
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Isaac E Stillman
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Kirk N Campbell
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY.
| | - Kristin Meliambro
- Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY.
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24
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Koirala A, Akilesh S, Jefferson JA. Collapsing Glomerulopathy. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:290-298. [PMID: 39084754 PMCID: PMC11296495 DOI: 10.1053/j.akdh.2024.03.008] [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: 06/26/2023] [Revised: 03/08/2024] [Accepted: 03/25/2024] [Indexed: 08/02/2024]
Abstract
Collapsing glomerulopathy (CG) is a pattern of kidney injury characterized by segmental or global collapse of the glomerular tuft associated with overlying epithelial cell hyperplasia. Although CG may be idiopathic, a wide range of etiologies have been identified that can lead to this pattern of injury. Recent advances have highlighted the role of inflammatory and interferon signaling pathways and upregulation of apolipoprotein L1 (APOL1) within podocytes in those carrying a high-risk APOL1 genotype. In this review, we describe the etiology, pathogenesis, pathology, and clinical course of CG, focusing on nonviral etiologies. We also describe current treatments and explore potential therapeutic options targeting interferon/APOL1 pathways in CG.
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Affiliation(s)
- Abbal Koirala
- Division of Nephrology, University of Washington, Seattle, Washington
| | - Shreeram Akilesh
- Department of Pathology, University of Washington, Seattle, Washington
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25
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Yau K, Kuah R, Cherney DZI, Lam TKT. Obesity and the kidney: mechanistic links and therapeutic advances. Nat Rev Endocrinol 2024; 20:321-335. [PMID: 38351406 DOI: 10.1038/s41574-024-00951-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/02/2024] [Indexed: 02/19/2024]
Abstract
Obesity is strongly associated with the development of diabetes mellitus and chronic kidney disease (CKD), but there is evidence for a bidirectional relationship wherein the kidney also acts as a key regulator of body weight. In this Review, we highlight the mechanisms implicated in obesity-related CKD, and outline how the kidney might modulate feeding and body weight through a growth differentiation factor 15-dependent kidney-brain axis. The favourable effects of bariatric surgery on kidney function are discussed, and medical therapies designed for the treatment of diabetes mellitus that lower body weight and preserve kidney function independent of glycaemic lowering, including sodium-glucose cotransporter 2 inhibitors, incretin-based therapies and metformin, are also reviewed. In summary, we propose that kidney function and body weight are related in a bidirectional fashion, and that this interrelationship affects human health and disease.
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Affiliation(s)
- Kevin Yau
- Division of Nephrology, Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Rachel Kuah
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, Toronto General Hospital, Toronto, Ontario, Canada.
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
- Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada.
| | - Tony K T Lam
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
- Toronto General Hospital Research Institute, UHN, Toronto, Ontario, Canada.
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26
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Chia-Gil A, Floege J, Stamellou E, Moeller MJ. Perihilar FSGS lesions originate from flat parietal epithelial cells. J Nephrol 2024; 37:1405-1409. [PMID: 38300433 PMCID: PMC11405489 DOI: 10.1007/s40620-024-01886-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 01/01/2024] [Indexed: 02/02/2024]
Affiliation(s)
- Arnaldo Chia-Gil
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
| | - Jürgen Floege
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
| | - Eleni Stamellou
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
- Department of Nephrology, University Hospital of Ioannina, Ioannina, Greece.
| | - Marcus J Moeller
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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27
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Mitrotti A, Giliberti M, Di Leo V, di Bari I, Pontrelli P, Gesualdo L. Hidden genetics behind glomerular scars: an opportunity to understand the heterogeneity of focal segmental glomerulosclerosis? Pediatr Nephrol 2024; 39:1685-1707. [PMID: 37728640 PMCID: PMC11026212 DOI: 10.1007/s00467-023-06046-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 05/02/2023] [Accepted: 05/30/2023] [Indexed: 09/21/2023]
Abstract
Focal segmental glomerulosclerosis (FSGS) is a complex disease which describes different kinds of kidney defects, not exclusively linked with podocyte defects. Since nephrin mutation was first described in association with early-onset nephrotic syndrome (NS), many advancements have been made in understanding genetic patterns associated with FSGS. New genetic causes of FSGS have been discovered, displaying unexpected genotypes, and recognizing possible site of damage. Many recent large-scale sequencing analyses on patients affected by idiopathic chronic kidney disease (CKD), kidney failure (KF) of unknown origin, or classified as FSGS, have revealed collagen alpha IV genes, as one of the most frequent sites of pathogenic mutations. Also, recent interest in complex and systemic lysosomal storage diseases, such as Fabry disease, has highlighted GLA mutations as possible causes of FSGS. Tubulointerstitial disease, recently classified by KDIGO based on genetic subtypes, when associated with UMOD variants, may phenotypically gain FSGS features, as well as ciliopathy genes or others, otherwise leading to completely different phenotypes, but found carrying pathogenic variants with associated FSGS phenotype. Thus, glomerulosclerosis may conceal different heterogeneous conditions. When a kidney biopsy is performed, the principal objective is to provide an accurate diagnosis. The broad spectrum of phenotypic expression and genetic complexity is demonstrating that a combined path of management needs to be applied. Genetic investigation should not be reserved only to selected cases, but rather part of medical management, integrating with clinical and renal pathology records. FSGS heterogeneity should be interpreted as an interesting opportunity to discover new pathways of CKD, requiring prompt genotype-phenotype correlation. In this review, we aim to highlight how FSGS represents a peculiar kidney condition, demanding multidisciplinary management, and in which genetic analysis may solve some otherwise unrevealed idiopathic cases. Unfortunately there is not a uniform correlation between specific mutations and FSGS morphological classes, as the same variants may be identified in familial cases or sporadic FSGS/NS or manifest a variable spectrum of the same disease. These non-specific features make diagnosis challenging. The complexity of FSGS genotypes requires new directions. Old morphological classification does not provide much information about the responsible cause of disease and misdiagnoses may expose patients to immunosuppressive therapy side effects, mistaken genetic counseling, and misguided kidney transplant programs.
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Affiliation(s)
- Adele Mitrotti
- Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy.
| | - Marica Giliberti
- Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Vincenzo Di Leo
- Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Ighli di Bari
- Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Paola Pontrelli
- Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Loreto Gesualdo
- Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
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28
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Bellur SS, Troyanov S, Vorobyeva O, Coppo R, Roberts ISD. Evidence from the large VALIGA cohort validates the subclassification of focal segmental glomerulosclerosis in IgA nephropathy. Kidney Int 2024; 105:1279-1290. [PMID: 38554992 DOI: 10.1016/j.kint.2024.03.011] [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: 08/10/2023] [Revised: 01/19/2024] [Accepted: 03/04/2024] [Indexed: 04/02/2024]
Abstract
Evidence from the Oxford IgA nephropathy (IgAN) cohort supports the clinical value of subclassifying focal segmental glomerulosclerosis lesions (S1). Using the larger Validation in IgA (VALIGA) study cohort, we investigated the association between podocytopathic changes and higher proteinuria, kidney outcome and response to immunosuppressive therapy. All biopsies were evaluated for glomeruli with segmental capillary occlusion by matrix ("not otherwise specified", NOS lesion), simple capsular adhesion without capillary occlusion (Adh), tip lesions, and podocyte hypertrophy (PH). S1 required a NOS lesion and/or Adh. A Chi-Squared Automatic Interaction Detection method was used to identify subgroups of FSGS lesions associated with distinctive proteinuria at biopsy. We assessed survival from a combined event (kidney failure or 50% decline in estimated glomerular filtration rate). Finally, we evaluated within each subgroup if immunosuppression was associated with a favorable outcome using propensity analysis. In 1147 patients, S1 was found in 70% of biopsies. Subclassification found NOS lesions in 44%, Adh in 59%, PH in 13%, and tip lesions in 3%, with much overlap. Four subgroups were identified with progressively higher proteinuria: from lowest, S1 without NOS, S1 with NOS but without Adh/PH, to highest, S1 with NOS and Adh but without PH, and S1 with NOS and PH. These four subgroups showed progressively worse kidney survival. Immunosuppression was associated with a better outcome only in the two highest proteinuria subgroups. Propensity analysis in these two groups, adjusted for clinical and pathological findings, found a significantly reduced time-dependent hazard of combined outcome with corticosteroids. Podocyte hypertrophy and glomeruli with simple adhesions appeared to reflect active lesions associated with a response to corticosteroids, while other S1 lesions defined chronicity. Thus, our findings support subclassifying S1 lesions in IgAN.
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Affiliation(s)
- Shubha S Bellur
- William Osler Health Systems Brampton & Queen's University, Kingston, Ontario, Canada
| | - Stéphan Troyanov
- Hôpital du Sacré-Coeur de Montréal, University of Montreal, Montreal, Quebec, Canada
| | - Olga Vorobyeva
- National Center of Clinical Morphological Diagnostics, Saint Petersburg, Russia
| | - Rosanna Coppo
- Fondazione Ricerca Molinette, Regina Margherita Hospital, Turin, Italy
| | - Ian S D Roberts
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
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29
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Bonilla M, Efe O, Selvaskandan H, Lerma EV, Wiegley N. A Review of Focal Segmental Glomerulosclerosis Classification With a Focus on Genetic Associations. Kidney Med 2024; 6:100826. [PMID: 38765809 PMCID: PMC11099322 DOI: 10.1016/j.xkme.2024.100826] [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] [Indexed: 05/22/2024] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) defines a distinct histologic pattern observed in kidney tissue that is linked to several distinct underlying causes, all converging on the common factor of podocyte injury. It presents a considerable challenge in terms of classification because of its varied underlying causes and the limited correlation between histopathology and clinical outcomes. Critically, precise nomenclature is key to describe and delineate the pathogenesis, subsequently guiding the selection of suitable and precision therapies. A proposed pathomechanism-based approach has been suggested for FSGS classification. This approach differentiates among primary, secondary, genetic, and undetermined causes, aiming to provide clarity. Genetic FSGS from monogenic mutations can emerge during childhood or adulthood, and it is advisable to conduct genetic testing in cases in which there is a family history of chronic kidney disease, nephrotic syndrome, or resistance to treatment. Genome-wide association studies have identified several genetic risk variants, such as those in apolipoprotein L1 (APOL1), that play a role in the development of FSGS. Currently, no specific treatments have been approved to treat genetic FSGS; however, interventions targeting underlying cofactor deficiencies have shown potential in some cases. Furthermore, encouraging results have emerged from a phase 2 trial investigating inaxaplin, a novel small molecule APOL1 channel inhibitor, in APOL1-associated FSGS.
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Affiliation(s)
- Marco Bonilla
- Section of Nephrology, Department of Medicine, University of Chicago, Chicago, IL
| | - Orhan Efe
- Division of Nephrology, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Haresh Selvaskandan
- IgA Mayer Nephropathy Laboratories, Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
- John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom
| | - Edgar V. Lerma
- Section of Nephrology, University of Illinois at Chicago/Advocate Christ Medical Center, Oak Lawn, IL
| | - Nasim Wiegley
- University of California Davis School of Medicine, Division of Nephrology, Sacramento, CA
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30
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Hao M, Lv Y, Liu S, Guo W. The New Challenge of Obesity - Obesity-Associated Nephropathy. Diabetes Metab Syndr Obes 2024; 17:1957-1971. [PMID: 38737387 PMCID: PMC11086398 DOI: 10.2147/dmso.s433649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 02/28/2024] [Indexed: 05/14/2024] Open
Abstract
In recent years, obesity has become one of the major diseases that affect human health and consume human health resources, especially when it causes comorbidities such as hypertension, diabetes, cardiovascular disease and kidney disease. Many studies have demonstrated that obesity is associated with the development of chronic kidney disease and can exacerbate the progression of end-stage renal disease. This review described the mechanisms associated with the development of obesity-associated nephropathy and the current relevant therapeutic modalities, with the aim of finding new therapeutic targets for obesity-associated nephropathy. The mechanisms of obesity-induced renal injury include, in addition to the traditional alterations in renal hemodynamics, the involvement of various mechanisms such as macrophage infiltration in adipose tissue, alterations in adipokines (leptin and adiponectin), and ectopic deposition of lipids. At present, there is no "point-to-point" treatment for obesity-induced kidney injury. The renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors and bariatric surgery described in this review can reduce urinary protein to varying degrees and delay the progression of kidney disease. In addition, recent studies on the therapeutic effects of intestinal flora on obesity may reduce the incidence of obesity-related kidney disease from the perspective of primary prevention. Both of these interventions have their own advantages and disadvantages, so the continuous search for the mechanism of obesity-induced related kidney disease will be extremely helpful for the future treatment of obesity-related kidney disease.
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Affiliation(s)
- Mengjin Hao
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China
- Department of Endocrinology, Jining No. 1 People’s Hospital, Jining, Shandong, 272000, People’s Republic of China
| | - You Lv
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China
| | - Siyuan Liu
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China
| | - Weiying Guo
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, 130021, People’s Republic of China
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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: 2] [Impact Index Per Article: 2.0] [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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Chávez Valencia V, Pérez-Vázquez V, Gómez García A, Vargas-Ortiz K, Villanueva Pérez MA, Godínez Rubí M, Pazarín Villaseñor L, Gutiérrez Castellanos S, Orizaga de la Cruz C. C4d expression in focal segmental glomerulosclerosis. Nefrologia 2024; 44:402-407. [PMID: 38906767 DOI: 10.1016/j.nefroe.2023.04.007] [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: 12/20/2022] [Revised: 03/22/2023] [Accepted: 04/10/2023] [Indexed: 06/23/2024] Open
Abstract
BACKGROUND There is a little information about of expression of C4d (complement fragment) in Focal segmental glomerulosclerosis (FSGS) subtypes. Our aim was to determine the expression of C4d in FSGS subtypes in percutaneous native renal biopsies in a second-level hospital and its correlation with clinical, biochemical and histological variables. MATERIAL AND METHODS A retrospective study in paraffin blocks of patients with biopsy with FSGS aged 16-65 years, indistinct sex, not diabetic or obese. Immunohistochemistry was performed for C4d and their expression was analyzing in non-sclerosed glomerular capillaries (GC) and sclerosis areas (SA). Clinical and biochemical variables were recorded. The cases were divided into C4d positive and C4d negative groups and compared. The correlation between C4d staining scores in CG and SA with clinical and biochemical variables were analyzed. RESULTS Twenty samples were analyzed, 4 for each subtype. At the time of biopsy average age 38.8 ± 18.6 years, 65% male, 8.7% were hypertension. The percentage of positivity for C4d was 40% in GC, 30% SA and 35% in mesangium. The highest expression was for cellular and collapsing subtypes. C4d positivity cases had increased proteinuria (p = 0.035). A significant correlation was found between percentage of C4d expression in CG with SA (p = 0.012) and SA with tubular atrophy and interstitial fibrosis (p < 0.05). CONCLUSIONS C4d expression in FSGS predominated in the cellular and collapsing subtypes, which translates complement activation. C4d is a possible surrogate marker in GSFS.
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Affiliation(s)
- Venice Chávez Valencia
- HGR No.1, Instituto Mexicano del Seguro Social, Morelia, Michoacán, Mexico; Departamento de Ciencias Médicas, División de Ciencias de la Salud, Campus León, Universidad de Guanajuato, León, Guanajuato, Mexico
| | - Victoriano Pérez-Vázquez
- Departamento de Ciencias Médicas, División de Ciencias de la Salud, Campus León, Universidad de Guanajuato, León, Guanajuato, Mexico.
| | - Anel Gómez García
- Centro de Investigación Biomédica de Michoacán, Instituto Mexicano del Seguro Social, Morelia, Michoacán, Mexico
| | - Katya Vargas-Ortiz
- Departamento de Ciencias Médicas, División de Ciencias de la Salud, Campus León, Universidad de Guanajuato, León, Guanajuato, Mexico
| | | | - Marisol Godínez Rubí
- Patología y Nefropatología, Centro de Diagnóstico e Investigación, Departamento de Morfología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
| | | | - Sergio Gutiérrez Castellanos
- Servicio de patología, Instituto Mexicano del Seguro Social, Centro Médico Nacional de Occidente (CMNO), Guadalajara, Jalisco, Mexico
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Chan L, Danyi Y, Chen C. A new index for the outcome of focal segmental glomerulosclerosis. Sci Rep 2024; 14:8278. [PMID: 38594302 PMCID: PMC11004142 DOI: 10.1038/s41598-024-59007-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 04/05/2024] [Indexed: 04/11/2024] Open
Abstract
Focal segmental glomerulosclerosis (FSGS) is a common pathological form of nephrotic syndrome. This study analyzed the value of pathological lesions and clinical prognosis of different segmental glomerulosclerosis ratios in FSGS. Two hundred and six FSGS patients were collected from Dec 2013 to Apr 2016. The patients were divided into two groups according to the proportion of glomerular segmental sclerosis: F1 (SSR ≤ 15%, n = 133) and F2 (SSR > 15%, n = 73). The clinical and pathological data were recorded and analyzed, and statistical differences were observed between the serum uric acid level and the percentage of chronic renal failure. The pathological results showed significant differences in interstitial fibrosis and tubular atrophy (IFTA), degree of mesangial hyperplasia, vascular lesions, synaptopodin intensity, and foot process effacement between the two groups. Multivariate logistic regression analysis showed significant differences in creatinine (OR: 1.008) and F2 group (OR: 1.19). In all patients, the prognoses of urine protein and serum creatinine levels were statistically different. Multivariate Cox regression analysis revealed that F2 (hazard ratio: 2.306, 95% CI 1.022-5.207) was associated with a risk of ESRD (end stage renal disease). The proportion of segmental glomerulosclerosis provides a guiding value in the pathological diagnosis and clinical prognosis of FSGS.
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Affiliation(s)
- Liu Chan
- International Medical Department, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Yang Danyi
- Department of Nephrology, The Second Xiangya Hospital, Central South University, No.139, Renmin Road, Changsha, 410011, Hunan, People's Republic of China.
- Hunan Key Laboratory of Kidney Disease and Blood, The Second Xiangya Hospital, Central South University, No.139, Renmin Road, Changsha, 410011, Hunan, People's Republic of China.
| | - Chao Chen
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People's Republic of China
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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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35
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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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Cambier A, Roy JP, Dossier C, Patey N, Rabant M, Boyer O, Delbet JD, Lapeyraque AL, Hogan J. IgA nephropathy in children with minimal proteinuria: to biopsy or not to biopsy? Pediatr Nephrol 2024; 39:781-787. [PMID: 37698655 DOI: 10.1007/s00467-023-06121-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 07/27/2023] [Accepted: 07/28/2023] [Indexed: 09/13/2023]
Abstract
BACKGROUND Tubulointerstitial lesions and glomerular inflammation severity have been shown to correlate with proteinuria in children with IgA nephropathy (cIgAN). However, there is a lack of data regarding severity of histopathologic findings in cIgAN in patients with minimal to absent proteinuria since kidney biopsy indications are not well defined in these cases. METHODS Twenty-eight cIgAN patients with kidney biopsy from 4 different centers in Paris (France) and Montreal (Canada) with a urine protein/creatinine ratio (UPCr) ≤ 0.03 g/mmol and a normal estimated glomerular filtration rate (eGFR > 90 ml/min/1.73 m2) on the day of kidney biopsy prior to treatment were included. RESULTS Median age was 11.82 (9.32-13.45) years, and median follow-up was 4 years (2.87-6.53). At time of biopsy, median eGFR was 116 (102.3-139.7) ml/min/1.73 m2, and median UPCr was 0.02 (0.011-0.03) g/mmol. Microscopic or macroscopic hematuria was present in 35.7% and 64.3% of cases, respectively. Kidney biopsy microscopy analysis showed mesangial (M1), endocapillary (E1), or extracapillary (C1) hypercellularity in 53.5%, 32.1%, and 7.1% of patients, respectively. Chronic histological lesions were also present: glomerulosclerosis (S1) in 42.8% and tubular atrophy/interstitial fibrosis in 7.1%. Podocytopathic features were detected in 21.4%. An ACE inhibitor or immunosuppressive therapy (IS) was prescribed in 42.8% and 21.4% of these patients respectively. One-third (35.7%) received no treatment. At last follow-up, median eGFR was 111.9 (90.47-136.1) ml/min/1.73 m2, and median UPCr was 0.028 (0.01-0.03) g/mmol. CONCLUSION cIgAN with minimal proteinuria at time of biopsy might be linked with acute and chronic glomerular lesions.
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Affiliation(s)
- Alexandra Cambier
- Division of Nephrology, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, QC, Canada.
- Sainte-Justine Hospital Pediatric Research Centre: Centre Hospitalier Universitaire Sainte-Justine Centre de Recherche, Montreal, QC, Canada.
| | - Jean-Philippe Roy
- Division of Nephrology, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, QC, Canada
| | - Claire Dossier
- Division of Nephrology, Hôpital Robert Debré, Paris, France
| | - Natacha Patey
- Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, QC, Canada
| | - Marion Rabant
- Division of Pathology, Hôpital Necker, Paris, France
| | - Olivia Boyer
- Néphrologie Pédiatrique, Centre de Référence MARHEA, Hôpital Necker-Enfants Malades, APHP, Centre, Institut Imagine, Inserm U1163, Université Paris Cité, Paris, France
| | | | - Anne-Laure Lapeyraque
- Division of Nephrology, Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, Montreal, QC, Canada
| | - Julien Hogan
- Division of Nephrology, Hôpital Robert Debré, Paris, France
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Neves PD, Watanabe A, Watanabe EH, Narcizo AM, Nunes K, Lerario AM, Ferreira FM, Cavalcante LB, Wongboonsin J, Malheiros DM, Jorge LB, Sampson MG, Noronha IL, Onuchic LF. Idiopathic collapsing glomerulopathy is associated with APOL1 high-risk genotypes or Mendelian variants in most affected individuals in a highly admixed population. Kidney Int 2024; 105:593-607. [PMID: 38143038 DOI: 10.1016/j.kint.2023.11.028] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 09/04/2023] [Accepted: 11/16/2023] [Indexed: 12/26/2023]
Abstract
Collapsing glomerulopathy (CG) is most often associated with fast progression to kidney failure with an incidence apparently higher in Brazil than in other countries. However, the reason for this occurrence is unknown. To better understand this, we performed an integrated analysis of clinical, histological, therapeutic, causative genetic and genetic ancestry data in a highly genetically admixed cohort of 70 children and adult patients with idiopathic CG (ICG). The disease onset occurred at 23 (interquartile range: 17-31) years and approximately half of patients progressed to chronic kidney disease requiring kidney replacement therapy (CKD-KRT) 36 months after diagnosis. Causative genetic bases, assessed by targeted-gene panel or whole-exome sequencing, were identified in 58.6% of patients. Among these cases, 80.5% harbored APOL1 high-risk genotypes (HRG) and 19.5% causative Mendelian variants (MV). Self-reported non-White patients more frequently had HRG. MV was an independent risk factor for progression to CKD-KRT by 36 months and the end of follow-up, while remission was an independent protective factor. All patients with HRG manifested CG at 9-44 years of age, whereas in those with APOL1 low-risk genotype, the disease arose throughout life. HRGs were associated with higher proportion of African genetic ancestry. Novel causative MVs were identified in COL4A5, COQ2 and PLCE1 and previously described causative MVs were identified in MYH9, TRPC6, COQ2, COL4A3 and TTC21B. Three patients displayed HRG combined with a variant of uncertain significance (ITGB4, LAMA5 or PTPRO). MVs were associated with worse kidney prognosis. Thus, our data reveal that the genetic status plays a major role in ICG pathogenesis, accounting for more than half of cases in a highly admixed Brazilian population.
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Affiliation(s)
- Precil D Neves
- Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil; Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil; Nephrology and Dialysis Center, Oswaldo Cruz German Hospital, São Paulo, Brazil
| | - Andreia Watanabe
- Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil; Division of Pediatric Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Elieser H Watanabe
- Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil; Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Amanda M Narcizo
- Large-Scale Sequencing Laboratory, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Kelly Nunes
- Human Genome Center, Institute of Biosciences/University of São Paulo, São Paulo, Brazil
| | - Antonio M Lerario
- Division of Endocrinology, University of Michigan, Ann Arbor, Michigan, USA
| | - Frederico M Ferreira
- Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Lívia B Cavalcante
- Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Janewit Wongboonsin
- Division of Pediatric Nephrology, Boston Children's Hospital, Boston, Massachusetts, USA; Division of Nephrology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Denise M Malheiros
- Department of Pathology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Lectícia B Jorge
- Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Matthew G Sampson
- Division of Pediatric Nephrology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Irene L Noronha
- Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Luiz F Onuchic
- Division of Nephrology, University of São Paulo School of Medicine, São Paulo, Brazil; Division of Molecular Medicine, University of São Paulo School of Medicine, São Paulo, Brazil.
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38
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Garnier AS, Laubacher H, Briet M. Drug-induced glomerular diseases. Therapie 2024; 79:271-281. [PMID: 37973491 DOI: 10.1016/j.therap.2023.10.010] [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: 06/30/2023] [Accepted: 09/18/2023] [Indexed: 11/19/2023]
Abstract
Drug-induced kidney diseases represent a wide range of diseases that are responsible for a significant proportion of all acute kidney injuries and chronic kidney diseases. In the present review, we focused on drug-induced glomerular diseases, more precisely podocytopathies - minimal change diseases (MCD), focal segmental glomerulosclerosis (FSGS) - and membranous nephropathies (MN), from a physiological and a pharmacological point of view. The glomerular filtration barrier is composed of podocytes that form foot processes tightly connected and directly in contact with the basal membrane and surrounding capillaries. The common clinical feature of these diseases is represented by the loss of the ability of the filtration barrier to retain large proteins, leading to massive proteinuria and nephrotic syndrome. Drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), D-penicillamine, tiopronin, trace elements, bisphosphonate, and interferons have been historically associated with the occurrence of MCD, FSGS, and MN. In the last ten years, the development of new anti-cancer agents, including tyrosine kinase inhibitors and immune checkpoint inhibitors, and research into their renal adverse effects highlighted these issues and have improved our comprehension of these diseases.
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Affiliation(s)
- Anne-Sophie Garnier
- Service de néphrologie-dialyse-transplantation, CHU d'Angers, 49000 Angers, France; UFR Santé, université d'Angers, 49000 Angers, France; Université d'Angers, UMR CNRS 6015, Inserm U1083, unité MitoVasc, Team Carme, SFR ICAT, 49000 Angers, France; Laboratoire MitoVasc, UMR Inserm 1083 CNRS 6215, 49000 Angers, France
| | - Hélène Laubacher
- UFR Santé, université d'Angers, 49000 Angers, France; Laboratoire MitoVasc, UMR Inserm 1083 CNRS 6215, 49000 Angers, France
| | - Marie Briet
- UFR Santé, université d'Angers, 49000 Angers, France; Université d'Angers, UMR CNRS 6015, Inserm U1083, unité MitoVasc, Team Carme, SFR ICAT, 49000 Angers, France; Laboratoire MitoVasc, UMR Inserm 1083 CNRS 6215, 49000 Angers, France; Service de pharmacologie - toxicologie et pharmacovigilance, CHU d'Angers, 49000 Angers, France.
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Chebotareva N, Vinogradov A, Birukova Y, Alentov I, Sergeeva N, Chemodanova D, Kononikhin AS, Moiseev SV. A pilot study of anti-nephrin antibodies in podocytopaties among adults. Nephrology (Carlton) 2024; 29:86-92. [PMID: 37864506 DOI: 10.1111/nep.14249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/17/2023] [Accepted: 10/04/2023] [Indexed: 10/23/2023]
Abstract
AIM Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are podocytopathies characterized by damage to the glomerular filtration barrier, leading to proteinuria and nephrotic syndrome. The production of anti-podocyte antibodies has been proposed as potential circulating factors contributing to the development of these conditions. The aim of the study is to evaluate the levels of anti-nephrin antibodies in patients with podocytopathies and healthy subjects. METHODS In this study, a total of 77 patients with active glomerulopathy and 11 healthy subjects were included. Forty one patients were diagnosed with FSGS, 11 with MCD, and 25 with MN. To measure the levels of anti-nephrin antibodies, enzyme-linked immunosorbent assay was used. RESULTS The levels of antibodies to nephrin were significantly higher in patients with MCD 61.2 [28.9-66.3] ng/mL and FSGS 32.5 [17.2-58.4] ng/mL compared to MN 20.3 [14.4-38.4] and healthy individuals 15.3 [12-18.9] ng/mL, p < .05. In patients with primary FSGS, the levels of antibodies to nephrin were significantly higher 45.2 [20-64.3] ng/mL compared to patients with secondary FSGS 26.7 [11.2-44.1] ng/mL, p < .05. There were no significant differences in the remission rate between the anti-nephrin antibodies positive and negative groups (log-rank test: p = .158). CONCLUSION The level of anti-nephrin antibodies was found to be significantly higher in patients with MCD and pFSGS compared to those with sFSGS, MN, and healthy subjects. Anti-nephrin antibodies in MCD and primary FSGS may be associated with the severity of podocytopathies, however they did not have an impact on the response to therapy.
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Affiliation(s)
- Natalia Chebotareva
- Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
| | | | - Yevgeniya Birukova
- Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Igor Alentov
- Department of Prediction of Conservative Treatment Efficiency, Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Natalia Sergeeva
- Department of Prediction of Conservative Treatment Efficiency, Hertsen Moscow Oncology Research Institute, Moscow, Russia
| | - Daria Chemodanova
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Alexey S Kononikhin
- Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Sergey V Moiseev
- Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
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Tuttle KR, Abner CW, Walker PD, Wang K, Rava A, Heo J, Bunke M. Clinical Characteristics and Histopathology in Adults With Focal Segmental Glomerulosclerosis. Kidney Med 2024; 6:100748. [PMID: 38196777 PMCID: PMC10772385 DOI: 10.1016/j.xkme.2023.100748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2024] Open
Abstract
Rationale & Objective Few data are available regarding histological features at the time of focal segmental glomerulosclerosis (FSGS) diagnosis among diverse real-world populations. This study describes clinical and histological characteristics and correlates of histological disease severity in adults with FSGS who underwent a clinical kidney biopsy. Study Design Real-world cohort study with data derived from health records. Setting & Participants Adults with FSGS by kidney biopsies from Arkana Laboratories from January 1, 2016 to May 31, 2020. Exposure Race, chronic kidney disease stage, nephrotic proteinuria, age, sex, and hypertension. Outcomes Severe histological disease, defined as global glomerulosclerosis in >50% of glomeruli and >25% interstitial fibrosis and tubular atrophy (IFTA). Analytical Approach Demographic, clinical, and histological characteristics were compared between race groups. Correlates of severe disease were analyzed using multiple logistic regression. Results Among 2,011 patients with FSGS, 40.6% were White, and 23.6% Black. White patients were older (52.8 vs 45.5 years, P < 0.001) with a higher estimated glomerular filtration rate (eGFR) than Black patients (53.5 vs 43.1 mL/min/1.73 m2, P < 0.001). A higher proportion of Black patients had global glomerulosclerosis ≥50% (32.1% vs 14.6%, P < 0.001) or IFTA >50% (34.6% vs 14.7%, P < 0.001). Severe histological disease was more likely in Black patients (OR, 2.46; 95% CI, 1.59-3.79; P < 0.001). A higher proportion of patients with nephrotic than nonnephrotic proteinuria exhibited diffuse foot process effacement. Limitations Unequal representation across United States regions, missing demographic and clinical data, and lack of data on primary versus secondary FSGS, treatments, or outcomes. Conclusions Black patients were more frequently diagnosed at younger age with lower eGFR and more severe histological disease compared with White patients. Timelier identification of FSGS could increase the opportunity for therapeutic intervention, especially for high-risk patients, to mitigate disease progression and complications. Plain-Language Summary Focal segmental glomerulosclerosis (FSGS) accounts for around one-quarter of diagnoses derived from clinical kidney biopsies in the United States. Limited data are available regarding the classes and distribution of histological features at FSGS diagnosis among diverse real-world populations. Analyzing data from US patients who underwent kidney biopsy and were diagnosed with FSGS, we showed that up to half of patients had features of severe histological disease. Of this overall population, Black patients were more frequently diagnosed at a younger age but with more severe histological disease than White patients. The work highlights the need for timelier diagnosis of FSGS to enable intervention at an earlier disease stage.
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Catanese L, Siwy J, Wendt R, Amann K, Beige J, Hendry B, Mischak H, Mullen W, Paterson I, Schiffer M, Wolf M, Rupprecht H. Differentiating primary and secondary FSGS using non-invasive urine biomarkers. Clin Kidney J 2024; 17:sfad296. [PMID: 38313685 PMCID: PMC10833144 DOI: 10.1093/ckj/sfad296] [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: 05/17/2023] [Indexed: 02/06/2024] Open
Abstract
Background Focal segmental glomerulosclerosis (FSGS) is divided into genetic, primary (p), uncertain cause, and secondary (s) forms. The subclasses differ in management and prognosis with differentiation often being challenging. We aimed to identify specific urine proteins/peptides discriminating between clinical and biopsy-proven pFSGS and sFSGS. Methods Sixty-three urine samples were collected in two different centers (19 pFSGS and 44 sFSGS) prior to biopsy. Samples were analysed using capillary electrophoresis-coupled mass spectrometry. For biomarker definition, datasets of age-/sex-matched normal controls (NC, n = 98) and patients with other chronic kidney diseases (CKDs, n = 100) were extracted from the urinary proteome database. Independent specificity assessment was performed in additional data of NC (n = 110) and CKD (n = 170). Results Proteomics data from patients with pFSGS were first compared to NC (n = 98). This resulted in 1179 biomarker (P < 0.05) candidates. Then, the pFSGS group was compared to sFSGS, and in a third step, pFSGS data were compared to data from different CKD etiologies (n = 100). Finally, 93 biomarkers were identified and combined in a classifier, pFSGS93. Total cross-validation of this classifier resulted in an area under the receiving operating curve of 0.95. The specificity investigated in an independent set of NC and CKD of other etiologies was 99.1% for NC and 94.7% for CKD, respectively. The defined biomarkers are largely fragments of different collagens (49%). Conclusion A urine peptide-based classifier that selectively detects pFSGS could be developed. Specificity of 95%-99% could be assessed in independent samples. Sensitivity must be confirmed in independent cohorts before routine clinical application.
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Affiliation(s)
- Lorenzo Catanese
- Department of Nephrology, Angiology and Rheumatology, Klinikum Bayreuth GmbH, Bayreuth, Germany
- Kuratorium for Dialysis and Transplantation (KfH) Bayreuth, Bayreuth, Germany
- Medizincampus Oberfranken, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | | | - Ralph Wendt
- Division of Nephrology, St. Georg Hospital Leipzig, Leipzig, Germany
| | - Kerstin Amann
- Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Joachim Beige
- Kuratorium for Dialysis and Transplantation (KfH) Renal Unit, Leipzig, Germany
- Department of Internal Medicine II, Martin-Luther-University Halle/Wittenberg, Halle/Saale, Germany
| | | | | | - William Mullen
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | | | - Mario Schiffer
- Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Research Center on Rare Kidney Diseases (RECORD), University Hospital Erlangen, Erlangen, Germany
| | | | - Harald Rupprecht
- Department of Nephrology, Angiology and Rheumatology, Klinikum Bayreuth GmbH, Bayreuth, Germany
- Kuratorium for Dialysis and Transplantation (KfH) Bayreuth, Bayreuth, Germany
- Medizincampus Oberfranken, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
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Yin DY, Hou GL, Yang XQ, Bi LL, Mei XF, Bai MK, Zhou L, Zhu S, Huang YJ. Urinary matrix metalloproteinase-7 is a sensitive biomarker to evaluate renal tubular injury in patients with minimal change disease and focal segmental glomerulosclerosis. Clin Kidney J 2024; 17:sfad027. [PMID: 38186883 PMCID: PMC10765092 DOI: 10.1093/ckj/sfad027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Indexed: 01/09/2024] Open
Abstract
Objective To explore the advantages of urinary matrix metalloproteinase-7 (MMP-7) in evaluating renal tubular injury in minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) patients compared with urinary cystatin C (CysC) and retinol-binding protein (RBP). Methods Serum and urine samples were collected from 20 healthy volunteers, and 40 MCD and 20 FSGS patients. Serum and urinary MMP-7 levels were measured by enzyme-linked immunosorbent assay. Urinary total protein, CysC and RBP levels were measured by automatic specific protein analyzer and compared with urinary creatinine level for calibration. The renal tissue serial sections were stained by MMP-7 immunohistochemistry and periodic acid-Schiff. Results Under light microscopy, MMP-7 granular weak positive expression was showed sporadically in the cytoplasm of a few renal tubular epithelial cells without obvious morphological changes in MCD patients, and MMP-7-positive expression was observed in the cytoplasm of some renal tubular epithelial cells in FSGS patients. There was no significant difference in serum MMP-7 level among the three groups. Compared with the control group, the urinary MMP-7 level in MCD patients was higher, but urinary CysC and RBP levels were not increased significantly. Compared with the control group and MCD patients, urinary MMP-7, CysC and RBP levels in FSGS patients were upregulated significantly. Conclusions Urinary MMP-7 could not only evaluate the mild renal tubular epithelial cells injury in MCD patients with massive proteinuria, but also evaluate the continuous renal tubular epithelial cells injury in FSGS patients.
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Affiliation(s)
- Dan-yang Yin
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Gai-ling Hou
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xiao-qing Yang
- Department of Pediatrics, The First Affiliated Hospital of Henan University of CM, Zhengzhou, Henan, China
| | - Liang-liang Bi
- Department of Pediatrics, The First Affiliated Hospital of Henan University of CM, Zhengzhou, Henan, China
| | - Xiao-feng Mei
- Department of Pediatrics, The First Affiliated Hospital of Henan University of CM, Zhengzhou, Henan, China
| | - Meng-ke Bai
- Department of Pediatrics, The First Affiliated Hospital of Henan University of CM, Zhengzhou, Henan, China
| | - Li Zhou
- School of Pharmacy China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Shan Zhu
- Department of Pediatrics, Henan Province Hospital of TCM, Zhengzhou, Henan, China
| | - Yan-jie Huang
- Department of Pediatrics, Henan University of Chinese Medicine, Zhengzhou, Henan, China
- Department of Pediatrics, The First Affiliated Hospital of Henan University of CM, Zhengzhou, Henan, China
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Liu W, Su ZH, Wan QJ. Proteinuria selectivity index in renal disease. Clin Chim Acta 2024; 552:117675. [PMID: 38007057 DOI: 10.1016/j.cca.2023.117675] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/16/2023] [Accepted: 11/20/2023] [Indexed: 11/27/2023]
Abstract
One of the main barriers to early detection and subsequent prevention of kidney diseases is the accessibility and feasibility of testing, especially in urine research. The proteinuria selectivity index (PSI or SI) is a method used to assess changes in glomerular permeability in glomerular diseases. It describes the pattern of proteinuria by comparing the clearance rates of large molecular proteins and transferrin, categorizing it as selective or non-selective. PSI is widely applied for kidney disease classification, prediction of corticosteroid efficacy, and prognosis. Herein, we reviewed the clinical applications and recent advancements of PSI in glomerular diseases, compared it with commonly used renal function biomarkers, and discussed the future research directions for PSI as a potential predictive marker for response to specific biologics.
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Affiliation(s)
- Wen Liu
- Department of Nephrology, the First Affiliated Hospital of Shenzhen University (Shenzhen Second People's Hospital), Shenzhen 518036, China
| | - Zhi-Hang Su
- Department of Nephrology, the First Affiliated Hospital of Shenzhen University (Shenzhen Second People's Hospital), Shenzhen 518036, China
| | - Qi-Jun Wan
- Department of Nephrology, the First Affiliated Hospital of Shenzhen University (Shenzhen Second People's Hospital), Shenzhen 518036, China.
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Ingelfinger JR. Sparsentan - Another Arrow in the Quiver for Treatment of FSGS? N Engl J Med 2023; 389:2482-2483. [PMID: 37921485 DOI: 10.1056/nejme2312324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2023]
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Thomasová D, Zelinová M, Libik M, Geryk J, Votýpka P, Rajnochová Bloudíčková S, Krejčí K, Reiterová J, Jančová E, Machová J, Kollárová M, Rychík I, Havrda M, Horáčková M, Putzová M, Šafránek R, Kollár M, Macek M. The most common founder pathogenic variant c.868G > A (p.Val290Met) in the NPHS2 gene in a representative adult Czech cohort with focal segmental glomerulosclerosis is associated with a milder disease and its underdiagnosis in childhood. Front Med (Lausanne) 2023; 10:1320054. [PMID: 38170106 PMCID: PMC10759319 DOI: 10.3389/fmed.2023.1320054] [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: 10/11/2023] [Accepted: 11/24/2023] [Indexed: 01/05/2024] Open
Abstract
Background Genetic focal segmental glomerulosclerosis (FSGS) is caused by pathogenic variants in a broad spectrum of genes that have a variable representation based on subjects' ethnicity and/or age. The most frequently mutated autosomal recessive gene in FSGS is NPHS2. In this study, we analyzed the spectrum of NPHS2 variants and their associated phenotype in Czech adult FSGS patients. Methods A representative cohort of 234 adult patients with FSGS, derived from 225 families originating from all regions of Czechia, was analyzed by massively parallel sequencing. In this study, we focused on the comprehensive analysis of the NPHS2 gene. The histological classification of FSGS followed the Columbia classification. Results We detected seven (3%) cases bearing homozygous or compound heterozygous pathogenic NPHS2 variants. A single pathogenic variant c.868G > A (p.Val290Met) was found in the majority of NPHS2-positive cases (86%; 6 out of 7) in histologically confirmed instances of FSGS. Its allele frequency among unrelated NPHS2-associated FSGS patients was 50% (6/12), and Haplotype analysis predicted its origin to be a result of a founder effect. There is an identical V290M-related haplotype on all V290M alleles spanning a 0,7 Mb region flanking NPHS2 in Central European FSGS populations. The phenotype of the p.Val290Met NPHS2-associated FSGS demonstrated a later onset and a much milder course of the disease compared to other NPHS2 pathogenic variants associated with FSGS. The mean age of the FSGS diagnosis based on kidney biopsy evaluation was 31.2 ± 7.46 years. In 50% of all cases, the initial disease manifestation of proteinuria occurred only in adulthood, with 83% of these cases not presenting with edemas. One-third (33%) of the studied subjects progressed to ESRD (2 out of 6) at the mean age of 35.0 ± 2.82 years. Conclusions We identified the most prevalent pathogenic variant, p.Val290Met, in the NPHS2 gene among Czech adult FSGS patients, which has arisen due to a founder effect in Central Europe. The documented milder course of the disease associated with this variant leads to the underdiagnosis in childhood. We established the histopathological features of the NPHS2-associated adult FSGS cases based on the Columbia classification. This might improve patient stratification and optimize their treatment.
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Affiliation(s)
- Dana Thomasová
- Institute of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University Prague, Prague, Czechia
| | - Michaela Zelinová
- Institute of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University Prague, Prague, Czechia
| | - Malgorzata Libik
- Institute of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University Prague, Prague, Czechia
| | - Jan Geryk
- Institute of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University Prague, Prague, Czechia
| | - Pavel Votýpka
- Institute of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University Prague, Prague, Czechia
| | | | - Karel Krejčí
- 3rd Department of Internal Medicine-Nephrology, Rheumatology and Endocrinology, University Hospital and Faculty of Medicine Palacký University Olomouc, Olomouc, Czechia
| | - Jana Reiterová
- Department of Nephrology, General University Hospital in Prague, First Faculty of Medicine, Charles University, Prague, Czechia
| | - Eva Jančová
- Department of Nephrology, General University Hospital in Prague, First Faculty of Medicine, Charles University, Prague, Czechia
| | - Jana Machová
- Department of Internal Medicine I, Faculty of Medicine in Pilsen, Charles University and Teaching Hospital, Pilsen, Czechia
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czechia
| | - Martina Kollárová
- Department of Internal Medicine, University Hospital Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Ivan Rychík
- Department of Internal Medicine, University Hospital Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Martin Havrda
- Department of Internal Medicine, University Hospital Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Miroslava Horáčková
- Department of Internal Medicine, University Hospital Motol and 2nd Faculty of Medicine, Charles University, Prague, Czechia
| | - Martina Putzová
- Biopticka Laboratory, Pilsen, Czechia
- Faculty of Medicine in Plzeň - Charles University, Pilsen, Czechia
| | - Roman Šafránek
- Department of Nephrology, University Hospital Hradec Králové, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czechia
| | - Marek Kollár
- Department of Pathology, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Milan Macek
- Institute of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University Prague, Prague, Czechia
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Taneda S, Honda K, Koike J, Ito N, Ishida H, Takagi T, Nagashima Y. Clinicopathological differences in focal segmental glomerulosclerosis depending on the accompanying pathophysiological conditions in renal allografts. Virchows Arch 2023; 483:809-819. [PMID: 37980299 DOI: 10.1007/s00428-023-03703-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/23/2023] [Accepted: 11/06/2023] [Indexed: 11/20/2023]
Abstract
Primary focal segmental glomerulosclerosis (FSGS) is thought to be caused by circulating factors leading to podocytopathy, whereas segmental sclerotic lesions (FSGS lesions) have several causes. We studied the clinicopathological differences of FSGS-lesions in 258 cases of FSGS in renal allografts, depending on the following accompanying pathophysiology: recurrence of primary FSGS, calcineurin inhibitor (CNI)-induced arteriolopathy, antibody-mediated rejection (ABMR), and other conditions. All cases were categorized with the Columbia classification. Recurrent FSGS developed the earliest after transplantation and showed the highest percentage of the collapsing (COL) variant in which collapse of the glomerular capillaries with epithelial hypertrophy was apparent. FSGS accompanying CNI-induced arteriolopathy predominantly developed the not otherwise specified (NOS) variant, showing severe ultrastructural endothelial injury. On the contrary, approximately 7% of the cases showed the COL variant, presenting glomerular endothelial damage such as double contours of glomerular basement membrane and endothelial cell swelling as well as epithelial cell proliferation. FSGS with ABMR had the highest creatinine levels and cellular variant percentage, with marked inflammation and ultrastructural endothelial injury. Approximately two-thirds of the cases without ABMR, CNI-induced arteriopathy, or recurrent FSGS had other coexisting conditions such as glomerulonephritis, T cell-mediated rejection, and reflux nephropathy with progressive tubulointerstitial fibrosis. Most of these cases were of the NOS variant. The clinicopathologic features of post-transplant FSGS differed depending on the associated conditions, and endothelial injury was apparent especially in cases of CNI-induced arteriolopathy and ABMR. Precise observation of FSGS lesions may facilitate the diagnosis and clinical management of FSGS during renal transplantation.
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Affiliation(s)
- Sekiko Taneda
- Department of Surgical Pathology, Tokyo Women's Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, 162-8666, Japan.
| | - Kazuho Honda
- Department of Anatomy, Showa University School of Medicine, Tokyo, Japan
| | - Junki Koike
- Department of Pathology, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan
| | - Naoko Ito
- Department of Surgical Pathology, Tokyo Women's Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, 162-8666, Japan
| | - Hideki Ishida
- Department of Organ Transplant Medicine, Tokyo Women's Medical University, Tokyo, Japan
| | - Toshio Takagi
- Department of Urology, Tokyo Women's Medical University, Tokyo, Japan
| | - Yoji Nagashima
- Department of Surgical Pathology, Tokyo Women's Medical University, 8-1, Kawada-Cho, Shinjuku-Ku, Tokyo, 162-8666, Japan
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Troyanov S, Jauhal A, Reich HN, Hladunewich MA, Cattran DC. Focal Segmental Glomerulosclerosis: Assessing the Risk of Relapse. Kidney Int Rep 2023; 8:2403-2415. [PMID: 38025232 PMCID: PMC10658237 DOI: 10.1016/j.ekir.2023.08.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/18/2023] [Accepted: 08/28/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Kidney outcomes are improved in primary focal segmental glomerulosclerosis (FSGS) by maintaining a remission in proteinuria. However, characteristics associated with relapses are uncertain. We sought to identify these by analyzing each remission. Methods We performed a retrospective study in patients with biopsy-proven lesions of FSGS, absent identifiable secondary cause, who had at least 1 remission from nephrotic-range proteinuria. In each patient, we identified every remission, every relapse, and their durations. Using a multilevel logistic regression to account for the clustering of multiple remissions within a patient, we tested which clinical characteristics were independently associated with relapses. Results In 203 individuals, 312 remissions occurred, 177 with and 135 without relapse. A minority of remissions were atypical, defined by either absent hypoalbuminemia and/or no immunosuppression (IS), in contrast to the classic nephrotic syndrome that remits with IS. Atypical remission variants were just as likely to relapse as the classical presentation. Only 24% of remission events were on maintenance therapy at relapse. Independent characteristics associated with relapses were higher maximal proteinuria while nephrotic; and in remission, higher nadir proteinuria, lower serum albumin, and higher blood pressure. Using these variables, we created a tool estimating the 1-year risk of relapse ranging from 9% to 80%, well-calibrated to the observed data. Conclusion In FSGS, relapses are frequent but predictable using independent clinical characteristics. We also provide evidence that atypical presentations remit and relapse following the same pattern as classic FSGS presentations. Treatment strategies to prolong remission duration should be addressed in future trials.
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Affiliation(s)
- Stéphan Troyanov
- Division of Nephrology, Department of Medicine, Hôpital du Sacré-Coeur de Montréal, University of Montréal, Montréal, Quebec, Canada
| | - Arenn Jauhal
- Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Heather N. Reich
- Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Michelle A. Hladunewich
- Division of Nephrology, Department of Medicine, Sunnybrook Health Science Center, University of Toronto, Toronto, Ontario, Canada
| | - Daniel C. Cattran
- Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Nikhil John E, Chellappan A, Ghodeshwar G, Sharma A, Chaudhari SR. Acute Myocardial Infarction in a Patient With Focal Segmental Glomerulosclerosis Tip Lesion: Hit With a Double Whammy. Cureus 2023; 15:e48860. [PMID: 38106743 PMCID: PMC10724038 DOI: 10.7759/cureus.48860] [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: 11/15/2023] [Indexed: 12/19/2023] Open
Abstract
Nephrotic syndrome is associated with venous and arterial thrombotic complications and is related to the imbalance between pro-thrombotic and anti-thrombotic factors. With an underlying nephrotic syndrome, arterial thromboses are infrequent, and coronary artery thromboses are much rarer. We present the case of a young male, with nephrotic syndrome, who suffered an acute anterior wall ST-segment elevation myocardial infarction. He was subsequently diagnosed to have focal segmental glomerulosclerosis (FSGS)-tip lesion. The patient was successfully managed with thrombolysis, steroids, anticoagulation, antiplatelets, and statins.
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Affiliation(s)
| | - Anand Chellappan
- Department of Nephrology, All India Institute of Medical Sciences, Nagpur, Nagpur, IND
| | - Gunjan Ghodeshwar
- Department of Cardiology, All India Institute of Medical Sciences, Nagpur, Nagpur, IND
| | - Alok Sharma
- Department of Renal Pathology, Dr. Lal PathLabs/National Reference Lab, New Delhi, IND
| | - Sachin R Chaudhari
- Department of Pathology, All India Institute of Medical Sciences, Nagpur, Nagpur, IND
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Scurt FG, Ernst A, FischerFröhlich CL, Schwarz A, Becker JU, Chatzikyrkou C. Performance of Scores Predicting Adverse Outcomes in Procurement Kidney Biopsies From Deceased Donors With Organs of Lower-Than-Average Quality. Transpl Int 2023; 36:11399. [PMID: 37901299 PMCID: PMC10600346 DOI: 10.3389/ti.2023.11399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 09/14/2023] [Indexed: 10/31/2023]
Abstract
Several scores have been devised for providing a prognosis of outcomes after kidney transplantation. This study is a comprehensive test of these scores in a cohort of deceased donors with kidneys of lower-than-average quality and procurement biopsies. In total, 15 scores were tested on a retrospective cohort consisting of 221 donors, 223 procurement biopsies, and 223 recipient records for performance on delayed graft function, graft function, or death-censored graft loss. The best-performing score for DGF was the purely clinical Chapal score (AUC 0.709), followed by the Irish score (AUC 0.684); for graft function, the Nyberg score; and for transplant loss, the Snoeijs score (AUC 0.630) and the Leuven scores (AUCs 0.637 and 0.620). The only score with an acceptable performance was the Chapal score. Its disadvantage is that knowledge of the cold ischemia time is required, which is not known at allocation. None of the other scores performed acceptably. The scores fared better in discarded kidneys than in transplanted kidneys. Our study shows an unmet need for practical prognostic scores useful at the time of a decision about discarding or accepting deceased donor kidneys of lower-than-average quality in the Eurotransplant consortium.
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Affiliation(s)
- Florian G. Scurt
- Faculty of Medicine, University Hospital Magdeburg, Magdeburg, Germany
| | - Angela Ernst
- University Hospital of Cologne, Cologne, Germany
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Besusparis J, Morkunas M, Laurinavicius A. A Spatially Guided Machine-Learning Method to Classify and Quantify Glomerular Patterns of Injury in Histology Images. J Imaging 2023; 9:220. [PMID: 37888327 PMCID: PMC10607091 DOI: 10.3390/jimaging9100220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 09/26/2023] [Accepted: 10/09/2023] [Indexed: 10/28/2023] Open
Abstract
Introduction The diagnosis of glomerular diseases is primarily based on visual assessment of histologic patterns. Semi-quantitative scoring of active and chronic lesions is often required to assess individual characteristics of the disease. Reproducibility of the visual scoring systems remains debatable, while digital and machine-learning technologies present opportunities to detect, classify and quantify glomerular lesions, also considering their inter- and intraglomerular heterogeneity. MATERIALS AND METHODS We performed a cross-validated comparison of three modifications of a convolutional neural network (CNN)-based approach for recognition and intraglomerular quantification of nine main glomerular patterns of injury. Reference values provided by two nephropathologists were used for validation. For each glomerular image, visual attention heatmaps were generated with a probability of class attribution for further intraglomerular quantification. The quality of classifier-produced heatmaps was evaluated by intersection over union metrics (IoU) between predicted and ground truth localization heatmaps. RESULTS A proposed spatially guided modification of the CNN classifier achieved the highest glomerular pattern classification accuracies, with area under curve (AUC) values up to 0.981. With regards to heatmap overlap area and intraglomerular pattern quantification, the spatially guided classifier achieved a significantly higher generalized mean IoU value compared to single-multiclass and multiple-binary classifiers. CONCLUSIONS We propose a spatially guided CNN classifier that in our experiments reveals the potential to achieve high accuracy for the localization of intraglomerular patterns.
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Affiliation(s)
- Justinas Besusparis
- Faculty of Medicine, Vilnius University, M.K.Ciurlionio 21, LT-03101 Vilnius, Lithuania; (M.M.); (A.L.)
- National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, P. Baublio 5, LT-08406 Vilnius, Lithuania
| | - Mindaugas Morkunas
- Faculty of Medicine, Vilnius University, M.K.Ciurlionio 21, LT-03101 Vilnius, Lithuania; (M.M.); (A.L.)
- National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, P. Baublio 5, LT-08406 Vilnius, Lithuania
| | - Arvydas Laurinavicius
- Faculty of Medicine, Vilnius University, M.K.Ciurlionio 21, LT-03101 Vilnius, Lithuania; (M.M.); (A.L.)
- National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Clinics, P. Baublio 5, LT-08406 Vilnius, Lithuania
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