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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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Nagano C, Hara S, Yoshikawa N, Takeda A, Gotoh Y, Hamada R, Matsuoka K, Yamamoto M, Fujinaga S, Sakuraya K, Kamei K, Hamasaki Y, Oguchi H, Araki Y, Ogawa Y, Okamoto T, Ito S, Tanaka S, Kaito H, Aoto Y, Ishiko S, Rossanti R, Sakakibara N, Horinouchi T, Yamamura T, Nagase H, Iijima K, Nozu K. Clinical, Pathological, and Genetic Characteristics in Patients with Focal Segmental Glomerulosclerosis. KIDNEY360 2022; 3:1384-1393. [PMID: 36176665 PMCID: PMC9416844 DOI: 10.34067/kid.0000812022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/27/2022] [Indexed: 01/11/2023]
Abstract
Background Approximately 30% of children with steroid-resistant nephrotic syndrome (SRNS) have causative monogenic variants. SRNS represents glomerular disease resulting from various etiologies, which lead to similar patterns of glomerular damage. Patients with SRNS mainly exhibit focal segmental glomerulosclerosis (FSGS). There is limited information regarding associations between histologic variants of FSGS (diagnosed using on the Columbia classification) and monogenic variant detection rates or clinical characteristics. Here, we report FSGS characteristics in a large population of affected patients. Methods This retrospective study included 119 patients with FSGS, diagnosed using the Columbia classification; all had been referred to our hospital for genetic testing from 2016 to 2021. We conducted comprehensive gene screening of all patients using a targeted next-generation sequencing panel that included 62 podocyte-related genes. Data regarding patients' clinical characteristics and pathologic findings were obtained from referring clinicians. We analyzed the associations of histologic variants with clinical characteristics, kidney survival, and gene variant detection rates. Results The distribution of histologic variants according to the Columbia classification was 45% (n=53) FSGS not otherwise specified, 21% (n=25) cellular, 15% (n=18) perihilar, 13% (n=16) collapsing, and 6% (n=7) tip. The median age at end stage kidney disease onset was 37 years; there were no differences in onset age among variants. We detected monogenic disease-causing variants involving 12 of the screened podocyte-related genes in 34% (40 of 119) of patients. The most common genes were WT1 (23%), INF2 (20%), TRPC6 (20%), and ACTN4 (10%). The perihilar and tip variants had the strongest and weakest associations with detection of monogenic variants (83% and 0%, respectively; P<0.001). Conclusions We revealed the distributions of histologic variants of genetic FSGS and nongenetic FSGS in a large patient population. Detailed data concerning gene variants and pathologic findings are important for understanding the etiology of FSGS.
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Affiliation(s)
- China Nagano
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shigeo Hara
- Department of Diagnostic Pathology, Kobe City Medical Center General Hospital, Kobe, Japan
| | | | - Asami Takeda
- Department of Nephrology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Yoshimitsu Gotoh
- Department of Pediatric Nephrology, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan
| | - Riku Hamada
- Department of Nephrology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan
| | - Kentaro Matsuoka
- Department of Pathology, Tokyo Metropolitan Children’s Medical Center, Tokyo, Japan
| | - Masaki Yamamoto
- Department of Pediatrics, Seirei-Hamamatsu General Hospital, Hamamatsu, Japan
| | - Shuichiro Fujinaga
- Division of Nephrology, Saitama Children’s Medical Center, Saitama, Japan
| | - Koji Sakuraya
- Division of Nephrology, Saitama Children’s Medical Center, Saitama, Japan
| | - Koichi Kamei
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Yuko Hamasaki
- Department of Nephrology, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Hideyo Oguchi
- Department of Nephrology, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Yoshinori Araki
- Department of Pediatric Nephrology, National Hospital Organization Hokkaido Medical Center, Hokkaido, Japan
| | - Yayoi Ogawa
- Hokkaido Renal Pathology Center, Sapporo, Japan
| | - Takayuki Okamoto
- Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shuichi Ito
- Department of Pediatrics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Seiji Tanaka
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Hiroshi Kaito
- Department of Nephrology, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan
| | - Yuya Aoto
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shinya Ishiko
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Rini Rossanti
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Nana Sakakibara
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomoko Horinouchi
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomohiko Yamamura
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroaki Nagase
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazumoto Iijima
- Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan,Department of Advanced Pediatric Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
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Kawaguchi T, Imasawa T, Kadomura M, Kitamura H, Maruyama S, Ozeki T, Katafuchi R, Oka K, Isaka Y, Yokoyama H, Sugiyama H, Sato H. Focal segmental glomerulosclerosis histologic variants and renal outcomes based on nephrotic syndrome, immunosuppression, and proteinuria remission. Nephrol Dial Transplant 2021; 37:1679-1690. [PMID: 34499164 DOI: 10.1093/ndt/gfab267] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The associations of focal segmental glomerulosclerosis (FSGS) histologic variants with renal outcomes have rarely been investigated comprehensively by clinically relevant subgroups in this modern age. METHODS Data on 304 (173 nephrotic and 131 non-nephrotic) patients with biopsy-confirmed FSGS from 2010 to 2013 were analyzed using the Japanese nationwide renal biopsy registry. The primary outcome was a composite of a 30% decline in estimated glomerular filtration rate or progression to end stage kidney disease 5 years from the biopsy. We compared outcomes of FSGS variants according to the Columbia classification using survival analyses. Subgroup analyses were performed based on nephrotic syndrome (NS), immunosuppression, and proteinuria remission (PR, proteinuria <0.3 g/day) during follow-up. Additionally, associations of NS, immunosuppression, and PR with outcomes were examined for each variant. RESULTS The distribution of variants was 48% (n = 145) FSGS not otherwise specified (NOS), 19% (n = 57) tip, 15% (n = 47) perihilar, 13% (n = 40) cellular, and 5% (n = 15) collapsing. The outcome event occurred in 87 patients (29%). No significant differences in the outcome were found among the variants. Subgroup analyses yielded similar results. However, there was a trend toward improved outcome in patients with PR irrespective of variants (hazard ratio adjusted for histologic variant and potential confounders [adjusted HR]: 0.19 [95% confidence interval (CI), 0.10-0.34]). NS was marginally associated with better outcome compared with non-NS (adjusted HR: 0.50 [95% CI, 0.25-1.01]. CONCLUSIONS FSGS variants alone might not have significant impacts on the renal outcome after 5 years, while PR could be predictive of improved renal prognosis for any variant. Specific strategies and interventions to achieve PR for each variant should be implemented for better renal outcomes.
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Affiliation(s)
- Takehiko Kawaguchi
- Department of Nephrology, National Hospital Organization Chibahigashi National Hospital, Chiba, Japan
| | - Toshiyuki Imasawa
- Department of Nephrology, National Hospital Organization Chibahigashi National Hospital, Chiba, Japan
| | - Moritoshi Kadomura
- Department of Nephrology, National Hospital Organization Chibahigashi National Hospital, Chiba, Japan
| | - Hiroshi Kitamura
- Department of Pathology, National Hospital Organization Chibahigashi National Hospital, Chiba, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Takaya Ozeki
- Department of Nephrology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | | | - Kazumasa Oka
- Department of Pathology, Prefectural Nishinomiya Hospital, Hyogo, Japan
| | - Yoshitaka Isaka
- Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hitoshi Yokoyama
- Department of Nephrology, Kanazawa Medical University School of Medicine, Ishikawa, Japan
| | - Hitoshi Sugiyama
- Department of Human Resource Development of Dialysis Therapy for Kidney Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroshi Sato
- Department of Internal Medicine, JR Sendai Hospital, Miyagi, Japan
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Role of the Histological Variant for the Prognosis and Course of the Focal Segmental Glomerulosclerosis. ACTA MEDICA BULGARICA 2021. [DOI: 10.2478/amb-2021-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Abstract
The focal segmental glomerulosclerosis is characterized by a morphological heterogeneity, most likely reflecting different pathogenetic mechanisms. The Colombian classification distinguishes five morphological types – non-specific (not otherwise specified or classical), perihilar, cellular, a tubular pole (tip) one and a collapsing one. Eighty-one (81) patients were studied. Their distribution according to the histological variant showed the highest frequency of the non-specific (classical) variant – 70.4%, followed by the perihilar variant – 27.20%, the cellular variant – 1.2% and the collapsing variant – 1.2%. No patients with tip lesions were identified. There were significant differences in the creatinine levels and the glomerular filtration rate (GFR) at the beginning and at the end of the follow-up between patients with the perihilar and the non-specific variants. Patients with the perihilar variant had a better treatment response with a high percentage of patients achieving complete remission – 59.1%. Patients with the non-specific variant had a high chance of treatment failure – 26.3% had no effect from treatment. The results of the study give grounds to assume that the histological variant affects the clinical picture, course and therapeutic response in patients with focal segmental glomerulosclerosis. It could be used as a prognostic marker of disease behavior and guide the clinician in treatment decisions.
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Tsuchimoto A, Matsukuma Y, Ueki K, Tanaka S, Masutani K, Nakagawa K, Mitsuiki K, Uesugi N, Katafuchi R, Tsuruya K, Nakano T, Kitazono T. Utility of Columbia classification in focal segmental glomerulosclerosis: renal prognosis and treatment response among the pathological variants. Nephrol Dial Transplant 2020; 35:1219-1227. [PMID: 30649467 DOI: 10.1093/ndt/gfy374] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 11/07/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The utility of the Columbia classification (Col-class) for focal segmental glomerulosclerosis (FSGS) has not yet been fully proven. METHODS We extracted 201 FSGS patients from 10 nephrology centers in Japan and investigated the difference of a composite renal endpoint, defined as doubling of serum creatinine and/or development of end-stage renal disease, in pathological variants. Sensitivity analysis was used to prove the utility of the Col-class to predict renal outcomes. Additionally, the renal protective effects of steroids and/or immunosuppression (steroid/IS) were investigated in patients stratified according to the Col-class. RESULTS The patients were classified into the following variants: not otherwise specified [NOS; n = 121 (60.1%)], perihilar [n = 31 (15.4%)], cellular [n = 19 (9.5%)], tip [n = 17 (8.5%)] and collapsing [n = 13 (6.5%)]. No tip variant patients reached the renal endpoint. The renal outcome in the collapsing variant was significantly poorer than that in the NOS [hazard ratio (HR) 3.71; P = 0.005]. In the sensitivity analysis, the area under the receiver operating characteristic curve for the renal endpoint was increased by adding Col-class to a model including common risk factors (P = 0.021). In a subgroup treated without steroid/IS, the outcome in the cellular variant was worse than that in the NOS (HR 5.10; P = 0.040) but the difference was not observed in the subgroup with steroid/IS (HR 0.54; P = 0.539). CONCLUSIONS The Col-class is useful to predict renal prognosis in Japanese patients with FSGS. In addition to good prognosis in the tip variant and poor in the collapsing variant, good clinical course in the cellular variant treated with steroid/IS was suggested.
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Affiliation(s)
- Akihiro Tsuchimoto
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuta Matsukuma
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenji Ueki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shigeru Tanaka
- Department of Internal Medicine, Fukuoka Dental College, Fukuoka, Japan
| | - Kosuke Masutani
- Division of Nephrology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | | | - Koji Mitsuiki
- Kidney Unit, Fukuoka Red Cross Hospital, Fukuoka, Japan
| | - Noriko Uesugi
- Department of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Ritsuko Katafuchi
- Kidney Unit, National Fukuoka Higashi Medical Center, Fukuoka, Japan
| | - Kazuhiko Tsuruya
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Integrated Therapy for Chronic Kidney Disease, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshiaki Nakano
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Genetic studies of focal segmental glomerulosclerosis: a waste of scientific time? Pediatr Nephrol 2020; 35:9-16. [PMID: 30591974 PMCID: PMC6901409 DOI: 10.1007/s00467-018-4161-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 11/27/2018] [Accepted: 11/28/2018] [Indexed: 12/21/2022]
Abstract
Many genetic causes of focal segmental glomerulosclerosis (FSGS) have been described. A paradox is that the science in the molecular biology, which generally appears of high quality, is not mirrored by a similarly critical analysis of the renal pathology. FSGS has been applied to such a wide range of conditions that it can reasonably be said to have no useful meaning. Attempts to refine the term have been largely ignored. Study of 252 papers on genetic causes of FSGS found various clinical features. Many papers took the reported diagnosis without question. Few papers reported a pathological review, almost half reported FSGS and up to six other conditions caused by any particular gene, some reported FSGS with recognisable glomerular disorders, over 80% did not apply the Columbia classification, and in nearly all with photomicrographs, the images were not useful for refinement of FSGS. Some workers commented on a lack of genotype-phenotype correlation. One reason is a disregard of the principle that scientific investigation requires an unambiguous definition of the condition studied, to allow others to replicate or refute the findings. Genetic studies of FSGS should use a similarly rigorous approach to renal pathology to that used in molecular biology.
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A bigenic mouse model of FSGS reveals perturbed pathways in podocytes, mesangial cells and endothelial cells. PLoS One 2019; 14:e0216261. [PMID: 31461442 PMCID: PMC6713350 DOI: 10.1371/journal.pone.0216261] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 08/12/2019] [Indexed: 11/24/2022] Open
Abstract
Focal segmental glomerulosclerosis is a major cause of end stage renal disease. Many patients prove unresponsive to available therapies. An improved understanding of the molecular basis of the disease process could provide insights leading to novel therapeutic approaches. In this study we carried out an RNA-seq analysis of the altered gene expression patterns of podocytes, mesangial cells and glomerular endothelial cells of the bigenic Cd2ap+/-, Fyn-/- mutant mouse model of FSGS. In the podocytes we observed upregulation of many genes related to the Tgfβ family/pathway, including Gdnf, Tgfβ1, Tgfβ2, Snai2, Vegfb, Bmp4, and Tnc. The mutant podocytes also showed upregulation of Acta2, a marker of smooth muscle and associated with myofibroblasts, which are implicated in driving fibrosis. GO analysis of the podocyte upregulated genes identified elevated protein kinase activity, increased expression of growth factors, and negative regulation of cell adhesion, perhaps related to the observed podocyte loss. Both podocytes and mesangial cells showed strong upregulation of aldehyde dehydrogenase genes involved in the synthesis of retinoic acid. Similarly, the Cd2ap+/-, Fyn-/- mesangial cells, as well as podocytes in other genetic models, and the glomeruli of human FSGS patients, all show upregulation of the serine protease Prss23, with the common thread suggesting important functionality. Another gene with strong upregulation in the Cd2ap+/-, Fyn-/- mutant mesangial cells as well as multiple other mutant mouse models of FSGS was thrombospondin, which activates the secreted inactive form of Tgfβ. The Cd2ap+/-, Fyn-/- mutant endothelial cells showed elevated expression of genes involved in cell proliferation, angioblast migration, angiogenesis, and neovasculature, all consistent with the formation of new blood vessels in the diseased glomerulus. The resulting global definition of the perturbed molecular pathways in the three major cell types of the mutant glomerulus provide deeper understanding of the molecular pathogenic pathways.
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Barisoni L, Gimpel C, Kain R, Laurinavicius A, Bueno G, Zeng C, Liu Z, Schaefer F, Kretzler M, Holzman LB, Hewitt SM. Digital pathology imaging as a novel platform for standardization and globalization of quantitative nephropathology. Clin Kidney J 2017; 10:176-187. [PMID: 28584625 PMCID: PMC5455257 DOI: 10.1093/ckj/sfw129] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 11/01/2016] [Indexed: 12/16/2022] Open
Abstract
The introduction of digital pathology to nephrology provides a platform for the development of new methodologies and protocols for visual, morphometric and computer-aided assessment of renal biopsies. Application of digital imaging to pathology made substantial progress over the past decade; it is now in use for education, clinical trials and translational research. Digital pathology evolved as a valuable tool to generate comprehensive structural information in digital form, a key prerequisite for achieving precision pathology for computational biology. The application of this new technology on an international scale is driving novel methods for collaborations, providing unique opportunities but also challenges. Standardization of methods needs to be rigorously evaluated and applied at each step, from specimen processing to scanning, uploading into digital repositories, morphologic, morphometric and computer-aided assessment, data collection and analysis. In this review, we discuss the status and opportunities created by the application of digital imaging to precision nephropathology, and present a vision for the near future.
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Affiliation(s)
- Laura Barisoni
- Department of Pathology, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Charlotte Gimpel
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Center for Pediatrics, Medical Center – University of Freiburg, Germany
| | - Renate Kain
- Clinical Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Arvydas Laurinavicius
- Faculty of Medicine and National Center of Pathology, Vilnius University, Vilnius, Lithuania
| | - Gloria Bueno
- VISILAB – E.T.S.I.I., University of Castilla-La Mancha, Ciudad Real, Spain
| | - Caihong Zeng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Franz Schaefer
- University Children Hospital, Pediatric Nephrology, Heidelberg, Germany
| | - Matthias Kretzler
- Department of Internal Medicine and Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
| | - Lawrence B. Holzman
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Stephen M. Hewitt
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA
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Abstract
Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g, glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g, to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.
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Affiliation(s)
- Avi Z. Rosenberg
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland; and
- Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Jeffrey B. Kopp
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland; and
- Kidney Disease Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
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Reproducibility of the NEPTUNE descriptor-based scoring system on whole-slide images and histologic and ultrastructural digital images. Mod Pathol 2016; 29:671-84. [PMID: 27102348 PMCID: PMC5515468 DOI: 10.1038/modpathol.2016.58] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 02/12/2016] [Accepted: 02/13/2016] [Indexed: 11/08/2022]
Abstract
The multicenter Nephrotic Syndrome Study Network (NEPTUNE) digital pathology scoring system employs a novel and comprehensive methodology to document pathologic features from whole-slide images, immunofluorescence and ultrastructural digital images. To estimate inter- and intra-reader concordance of this descriptor-based approach, data from 12 pathologists (eight NEPTUNE and four non-NEPTUNE) with experience from training to 30 years were collected. A descriptor reference manual was generated and a webinar-based protocol for consensus/cross-training implemented. Intra-reader concordance for 51 glomerular descriptors was evaluated on jpeg images by seven NEPTUNE pathologists scoring 131 glomeruli three times (Tests I, II, and III), each test following a consensus webinar review. Inter-reader concordance of glomerular descriptors was evaluated in 315 glomeruli by all pathologists; interstitial fibrosis and tubular atrophy (244 cases, whole-slide images) and four ultrastructural podocyte descriptors (178 cases, jpeg images) were evaluated once by six and five pathologists, respectively. Cohen's kappa for inter-reader concordance for 48/51 glomerular descriptors with sufficient observations was moderate (0.40<kappa≤0.60) for 17 and good (0.60<kappa≤0.80) for 8, for 52% with moderate or better kappas. Clustering of glomerular descriptors based on similar pathologic features improved concordance. Concordance was independent of years of experience, and increased with webinar cross-training. Excellent concordance was achieved for interstitial fibrosis and tubular atrophy. Moderate-to-excellent concordance was achieved for all ultrastructural podocyte descriptors, with good-to-excellent concordance for descriptors commonly used in clinical practice, foot process effacement, and microvillous transformation. NEPTUNE digital pathology scoring system enables novel morphologic profiling of renal structures. For all histologic and ultrastructural descriptors tested with sufficient observations, moderate-to-excellent concordance was seen for 31/54 (57%). Descriptors not sufficiently represented will require further testing. This study proffers the NEPTUNE digital pathology scoring system as a model for standardization of renal biopsy interpretation extendable outside the NEPTUNE consortium, enabling international collaborations.
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Practical Application of Columbia Classification for Focal Segmental Glomerulosclerosis. BIOMED RESEARCH INTERNATIONAL 2016; 2016:9375753. [PMID: 27247945 PMCID: PMC4876206 DOI: 10.1155/2016/9375753] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2015] [Accepted: 04/06/2016] [Indexed: 11/29/2022]
Abstract
Focal segmental glomerulosclerosis (FSGS) is a heterogeneous clinicopathological entity. Two frameworks for the classification of FSGS have been described: etiologic and morphologic. The etiologic classification is distinguished among genetic, adaptive, virus-associated, drug-induced, and idiopathic types. Morphologic classification is commonly referred to as the Columbia classification published in 2004, which distinguishes five variants: collapsing, tip, cellular, perihilar, and not otherwise specified (NOS). This classification is based on light microscopic patterns with rigorously defined specific criteria, which can be applied to primary and secondary forms of FSGS, and has been widely used over the past 10 years both as a diagnostic and as a prognostic clinical tool. This paper defines common histopathological features of FSGS, distinguished characters among five variants, and points out the confusion about terminology of variants, because most were proposed in the past with different definitions. Despite good interobserver reproducibility of this classification system, difficulty in its application may arise in the interpretation of lesions with mixed features of more than one variant in the same tissue specimen and with late lesions, because other variants may evolve into the NOS variant over time.
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Zhong Y, Xu F, Li X, Chen H, Liang S, Zhu X, Liu Z, Zeng C. The evolution of morphological variants of focal segmental glomerulosclerosis: a repeat biopsy-based observation. Nephrol Dial Transplant 2015; 31:87-95. [PMID: 26160893 DOI: 10.1093/ndt/gfv245] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 05/13/2015] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND The Columbia classification employs a systematic, hierarchical approach to define five mutually exclusive variants. Studies have demonstrated differences in baseline clinical characteristics and outcomes among the Columbia classification variants. However, the evolution of the Columbia classification variants of primary focal segmental glomerulosclerosis (FSGS) is unclear. We assessed the evolution of morphological variants in FSGS based on repeat native renal biopsies. METHODS Twenty-four patients (18 male, 6 female) with idiopathic FSGS who underwent more than one renal biopsy were enrolled in this study; three of these patients underwent three renal biopsies. The patients' clinicopathological features were reviewed. The subtypes of FSGS (2004 Columbia classification) included the collapsing, tip, cellular, perihilar and not otherwise specified (NOS) variants. The evolution of the Columbia classification variants of primary FSGS in each patient was evaluated. RESULTS The interval between the first and second renal biopsy was 21.95 ± 24.33 months. No significant differences in laboratory data were noted between the first and second renal biopsy. At the first renal biopsy, 5 patients were classified with collapsing, 5 with tip, 6 with cellular, 2 with perihilar and 6 with NOS variants. At the second renal biopsy, 3 patients were classified with collapsing, 3 with tip lesion, 4 with cellular, 1 with perihilar and 13 with NOS variants. Subtype changes from the first to repeat biopsies occurred in 11 patients, 9 of which progressed from other variants to the NOS variant. CONCLUSION Repeat renal biopsies are a useful tool for observing FSGS histological changes. The transformation from other subtypes to the NOS variant was the most common change; these alterations were accompanied by clinical progression.
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Affiliation(s)
- Yongzhong Zhong
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School Of Medicine, Nanjing 210002, P.R. China
| | - Feng Xu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School Of Medicine, Nanjing 210002, P.R. China
| | - Xiaomei Li
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School Of Medicine, Nanjing 210002, P.R. China
| | - Hao Chen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School Of Medicine, Nanjing 210002, P.R. China
| | - Shaoshan Liang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School Of Medicine, Nanjing 210002, P.R. China
| | - Xiaodong Zhu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School Of Medicine, Nanjing 210002, P.R. China
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School Of Medicine, Nanjing 210002, P.R. China
| | - Caihong Zeng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School Of Medicine, Nanjing 210002, P.R. China
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The Impact of Histologic Variants on FSGS Outcomes. INTERNATIONAL SCHOLARLY RESEARCH NOTICES 2014; 2014:913690. [PMID: 27437509 PMCID: PMC4897537 DOI: 10.1155/2014/913690] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 09/04/2014] [Indexed: 01/25/2023]
Abstract
Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disease leading to end-stage renal disease. The clinical course is highly variable with disparate responses to therapeutic intervention and rates of progression. Histologic variant subtype has been commonly used as a prognostic and therapeutic guide in the clinical management of FSGS. The tip lesion is widely considered to portend the most favorable prognosis and to be the most responsive to steroid therapy. Conversely, the collapsing lesion, more prevalent in patients of African descent, is associated with steroid resistance and higher risk of disease progression. In the 10 years since the Columbia classification system for FSGS was published, some retrospective and one prospective study explored the impact of histologic variants at the time of biopsy on FSGS outcomes. The results largely validate its clinical predictive value with respect to treatment response, though its utility in cases recurring after kidney transplantation is still unknown. Sampling and interpretation errors are additional sources of caution. More research is needed to fully define reproducible prognostic and therapeutic markers for this polymorphic disorder.
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Abstract
Kidney diseases are morphologically heterogeneous. Pathologic classifications of renal disease permit standardization of diagnosis and may identify clinical-pathologic subgroups with different outcomes and/or responses to treatment. To date, classifications have been proposed for lupus nephritis, allograft rejection, IgA nephropathy, focal segmental glomerulosclerosis, antineutrophil cytoplasmic antibody -related glomerulonephritis, and diabetic glomerulosclerosis. These classifications share several limitations related to lack of specificity, reproducibility, validation, and relevance to clinical practice. They offer a standardized approach to diagnosis, however, which should facilitate communication and clinical research.
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Affiliation(s)
- M Barry Stokes
- Department of Pathology, Columbia University College of Physicians and Surgeons, 630 West 168th Street, VC14-224, New York, NY 10032, USA.
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Stokes MB, D'Agati VD. Morphologic variants of focal segmental glomerulosclerosis and their significance. Adv Chronic Kidney Dis 2014; 21:400-7. [PMID: 25168828 DOI: 10.1053/j.ackd.2014.02.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Accepted: 02/05/2014] [Indexed: 11/11/2022]
Abstract
Focal segmental glomerulosclerosis (FSGS) comprises a group of clinical-pathologic syndromes characterized by heavy proteinuria and segmental obliteration of glomerular capillaries by extracellular matrix. FSGS lesions display morphologic heterogeneity with respect to their relationship to the glomerular vascular and tubular poles, the presence of capillary collapse, and endocapillary and extracapillary hypercellularity. A working proposal, commonly referred to as the Columbia Classification, distinguishes 5 mutually exclusive morphologic variants: collapsing, tip, cellular, perihilar, and not otherwise specified (NOS), which can be applied to primary and secondary forms of FSGS. Several studies have documented significant differences in baseline clinical characteristics and outcomes between morphologic variants of primary FSGS, supporting that this classification may provide useful prognostic information. The association of certain variants with particular secondary causes of FSGS suggests pathogenetic relevance.
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Choi MJ. Histologic Classification of FSGS: Does Form Delineate Function? Clin J Am Soc Nephrol 2013; 8:344-6. [DOI: 10.2215/cjn.00660113] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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