Journal Article
. 2013 Feb; 8(8):1449-59.
doi: 10.2215/CJN.08370812.

Digital pathology evaluation in the multicenter Nephrotic Syndrome Study Network (NEPTUNE)

Laura Barisoni 1 Cynthia C Nast  J Charles Jennette  Jeffrey B Hodgin  Andrew M Herzenberg  Kevin V Lemley  Catherine M Conway  Jeffrey B Kopp  Matthias Kretzler  Christa Lienczewski  Carmen Avila-Casado  Serena Bagnasco  Sanjeev Sethi  John Tomaszewski  Adil H Gasim  Stephen M Hewitt  
  • PMID: 23393107
  •     23 References
  •     48 citations


Pathology consensus review for clinical trials and disease classification has historically been performed by manual light microscopy with sequential section review by study pathologists, or multi-headed microscope review. Limitations of this approach include high intra- and inter-reader variability, costs, and delays for slide mailing and consensus reviews. To improve this, the Nephrotic Syndrome Study Network (NEPTUNE) is systematically applying digital pathology review in a multicenter study using renal biopsy whole slide imaging (WSI) for observation-based data collection. Study pathology materials are acquired, scanned, uploaded, and stored in a web-based information system that is accessed through a web-browser interface. Quality control includes metadata and image quality review. Initially, digital slides are annotated, with each glomerulus identified, given a unique number, and maintained in all levels until the glomerulus disappears or sections end. The software allows viewing and annotation of multiple slide sections concurrently. Analysis utilizes "descriptors" for patterns of injury, rather than diagnoses, in renal parenchymal compartments. This multidimensional representation via WSI, allows more accurate glomerular counting and identification of all lesions in each glomerulus, with data available in a searchable database. The use of WSI brings about efficiency critical to pathology review in a clinical trial setting, including independent review by multiple pathologists, improved intraobserver and interobserver reproducibility, efficiencies and risk reduction in slide circulation and mailing, centralized management of data integrity and slide images for current or future studies, and web-based consensus meetings. The overall effect is improved incorporation of pathology review in a budget neutral approach.

An electron microscope study of the glomerulus in nephrosis, glomerulonephritis, and lupus erythematosus.
J Exp Med, 1957 Nov 01; 106(5). PMID: 13475621    Free PMC article.
Highly Cited.
Novel quantitative method to evaluate globotriaosylceramide inclusions in renal peritubular capillaries by virtual microscopy in patients with fabry disease.
Laura Barisoni, J Charles Jennette, +5 authors, Pol Boudes.
Arch Pathol Lab Med, 2012 Jun 30; 136(7). PMID: 22742555
The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.
Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, Ian S D Roberts, +42 authors, Hong Zhang.
Kidney Int, 2009 Jul 03; 76(5). PMID: 19571790
Highly Cited.
Immunologic aspects of renal disease.
N Engl J Med, 1959 Dec 17; 261. PMID: 13848323
Superiority of virtual microscopy versus light microscopy in transplantation pathology.
Yasemin Ozluk, Paula L Blanco, +3 authors, Banu Sis.
Clin Transplant, 2011 Oct 01; 26(2). PMID: 21955102
Reports of Medical Cases, Selected with a View of Illustrating the Symptoms and Cure of Diseases, by a Reference to Morbid Anatomy.
Med Chir Rev, 1831 Jul 01; 15(30). PMID: 29918205    Free PMC article.
Highly Cited. Review.
Pathologic classification of focal segmental glomerulosclerosis: a working proposal.
Vivette D D'Agati, Agnes B Fogo, Jan A Bruijn, J Charles Jennette.
Am J Kidney Dis, 2004 Jan 30; 43(2). PMID: 14750104
Highly Cited.
Advances in the biology and genetics of the podocytopathies: implications for diagnosis and therapy.
Laura Barisoni, H William Schnaper, Jeffrey B Kopp.
Arch Pathol Lab Med, 2009 Feb 07; 133(2). PMID: 19195964    Free PMC article.
Histochemical demonstration of the in vivo localization of antibodies: antigenic components of the kidney and the pathogenesis of glomerulonephritis.
J Histochem Cytochem, 1955 Jul 01; 3(4). PMID: 13242786
Three-dimensional analysis of glomerular morphology in patients with subtotal nephrectomy.
A Remuzzi, M Mazerska, +3 authors, G Remuzzi.
Kidney Int, 1995 Jul 01; 48(1). PMID: 7564072
Pathologic classification of diabetic nephropathy.
Thijs W Cohen Tervaert, Antien L Mooyaart, +14 authors, Renal Pathology Society.
J Am Soc Nephrol, 2010 Feb 20; 21(4). PMID: 20167701
Highly Cited.
Utility of whole slide imaging and virtual microscopy in prostate pathology.
Philippe Camparo, Lars Egevad, +12 authors, Murali Varma.
APMIS, 2012 Mar 21; 120(4). PMID: 22429212
Aspiration biopsy of the kidney.
Am J Med, 1951 Sep 01; 11(3). PMID: 14877837
Highly Cited.
Histopathologic classification of ANCA-associated glomerulonephritis.
Annelies E Berden, Franco Ferrario, +9 authors, Ingeborg M Bajema.
J Am Soc Nephrol, 2010 Jul 10; 21(10). PMID: 20616173
Highly Cited.
History of the Banff classification of allograft pathology as it approaches its 20th year.
Kim Solez.
Curr Opin Organ Transplant, 2009 Dec 02; 15(1). PMID: 19949334
The classification of glomerulonephritis in systemic lupus erythematosus revisited.
Jan J Weening, Vivette D D'Agati, +20 authors, Michio Nagata.
J Am Soc Nephrol, 2004 Jan 30; 15(2). PMID: 14747370
Highly Cited.
Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach.
Crystal A Gadegbeku, Debbie S Gipson, +37 authors, Matthias Kretzler.
Kidney Int, 2013 Jan 18; 83(4). PMID: 23325076    Free PMC article.
Highly Cited.
Telepathology and the networking of pathology diagnostic services.
R S Weinstein, K J Bloom, L S Rozek.
Arch Pathol Lab Med, 1987 Jul 01; 111(7). PMID: 3606341
The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.
Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, Daniel C Cattran, +43 authors, Hong Zhang.
Kidney Int, 2009 Jul 03; 76(5). PMID: 19571791
Highly Cited.
Digital pathology evaluation of complement C4d component deposition in the kidney allograft biopsies is a useful tool to improve reproducibility of the scoring.
Ernesta Brazdziute, Arvydas Laurinavicius.
Diagn Pathol, 2011 Apr 22; 6 Suppl 1. PMID: 21489200    Free PMC article.
Cyclosporine induces glomerulosclerosis: three-dimensional definition of the lesions in a rat model of renal transplant.
N Perico, A Detcheva, E I Khalil, G Remuzzi.
Kidney Int, 1996 May 01; 49(5). PMID: 8731092
Aspiration biopsy of the kidney, including i.a. a report of a case of amyloidosis diagnosed through aspiration biopsy of the kidney in 1944 and investigated at an autopsy in 1950.
Acta Med Scand, 1952 Sep 29; 143(6). PMID: 12976034
A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases.
Laura Barisoni, H William Schnaper, Jeffrey B Kopp.
Clin J Am Soc Nephrol, 2007 Aug 19; 2(3). PMID: 17699461
Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma.
R Mark Simpson, Boris C Bastian, +20 authors, Stephen M Hewitt.
Pigment Cell Melanoma Res, 2013 Oct 17; 27(1). PMID: 24128326    Free PMC article.
Histological quantitation of brain injury using whole slide imaging: a pilot validation study in mice.
Zhenzhou Chen, Dmitriy Shin, +8 authors, Zezong Gu.
PLoS One, 2014 Mar 19; 9(3). PMID: 24637518    Free PMC article.
Defining nephrotic syndrome from an integrative genomics perspective.
Matthew G Sampson, Jeffrey B Hodgin, Matthias Kretzler.
Pediatr Nephrol, 2014 Jun 04; 30(1). PMID: 24890338    Free PMC article.
Kidney disease: new technologies translate mechanisms to cure.
John F O'Toole, John R Sedor.
J Clin Invest, 2014 Jun 04; 124(6). PMID: 24892702    Free PMC article.
Pro: 'The usefulness of biomarkers in glomerular diseases'. The problem: moving from syndrome to mechanism--individual patient variability in disease presentation, course and response to therapy.
Laura H Mariani, Matthias Kretzler.
Nephrol Dial Transplant, 2015 May 23; 30(6). PMID: 25994659    Free PMC article.
Integrative Genomics Identifies Novel Associations with APOL1 Risk Genotypes in Black NEPTUNE Subjects.
Matthew G Sampson, Catherine C Robertson, +20 authors, Nephrotic Syndrome Study Network.
J Am Soc Nephrol, 2015 Jul 08; 27(3). PMID: 26150607    Free PMC article.
Highly Cited.
Introduction: Precision Medicine for Glomerular Disease: The Road Forward.
Matthias Kretzler, John R Sedor.
Semin Nephrol, 2015 Jul 29; 35(3). PMID: 26215858    Free PMC article.
Morphology in the Digital Age: Integrating High-Resolution Description of Structural Alterations With Phenotypes and Genotypes.
Cynthia C Nast, Kevin V Lemley, +4 authors, Laura Barisoni.
Semin Nephrol, 2015 Jul 29; 35(3). PMID: 26215864    Free PMC article.
Research Infrastructure for Collaborative Team Science: Challenges in Technology-Supported Workflows in and Across Laboratories, Institutions, and Geographies.
Barbara Mirel, Airong Luo, Marcelline Harris.
Semin Nephrol, 2015 Jul 29; 35(3). PMID: 26215866    Free PMC article.
Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker.
Wenjun Ju, Viji Nair, +31 authors, ERCB, C-PROBE, NEPTUNE, and PKU-IgAN Consortium.
Sci Transl Med, 2015 Dec 04; 7(316). PMID: 26631632    Free PMC article.
Highly Cited.
Complete Remission in the Nephrotic Syndrome Study Network.
Debbie S Gipson, Jonathan P Troost, +51 authors, Matthias Kretzler.
Clin J Am Soc Nephrol, 2015 Dec 15; 11(1). PMID: 26656320    Free PMC article.
Clinical Neuropathology Views - 2/2016: Digital networking in European neuropathology: An initiative to facilitate truly interactive consultations.
Miguel A Idoate, Marcial García-Rojo.
Clin Neuropathol, 2016 Feb 03; 35(2). PMID: 26833552    Free PMC article.
APOL1-G0 or APOL1-G2 Transgenic Models Develop Preeclampsia but Not Kidney Disease.
Leslie A Bruggeman, Zhenzhen Wu, +7 authors, John F O'Toole.
J Am Soc Nephrol, 2016 Mar 31; 27(12). PMID: 27026370    Free PMC article.
Highly Cited.
Reproducibility of the NEPTUNE descriptor-based scoring system on whole-slide images and histologic and ultrastructural digital images.
Laura Barisoni, Jonathan P Troost, +18 authors, Stephen M Hewitt.
Mod Pathol, 2016 Apr 23; 29(7). PMID: 27102348    Free PMC article.
Morphometry Predicts Early GFR Change in Primary Proteinuric Glomerulopathies: A Longitudinal Cohort Study Using Generalized Estimating Equations.
Kevin V Lemley, Serena M Bagnasco, +4 authors, Peter X K Song.
PLoS One, 2016 Jun 11; 11(6). PMID: 27285824    Free PMC article.
The Application of Digital Pathology to Improve Accuracy in Glomerular Enumeration in Renal Biopsies.
Avi Z Rosenberg, Matthew Palmer, +11 authors, Stephen M Hewitt.
PLoS One, 2016 Jun 17; 11(6). PMID: 27310011    Free PMC article.
Diagnosing Pathological Prognostic Factors in Retinoblastoma: Correlation between Traditional Microscopy and Digital Slides.
Pablo Zoroquiain, Patrick Logan, +4 authors, Miguel N Burnier.
Ocul Oncol Pathol, 2016 Jun 30; 1(4). PMID: 27354984    Free PMC article.
Human Factors and Human-Computer Considerations in Teleradiology and Telepathology.
Elizabeth A Krupinski.
Healthcare (Basel), 2014 Jan 01; 2(1). PMID: 27429262    Free PMC article.
Defining Glomerular Disease in Mechanistic Terms: Implementing an Integrative Biology Approach in Nephrology.
Laura H Mariani, William F Pendergraft, Matthias Kretzler.
Clin J Am Soc Nephrol, 2016 Sep 16; 11(11). PMID: 27630182    Free PMC article.
Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies.
Laura H Mariani, Sebastian Martini, +14 authors, Serena M Bagnasco.
Nephrol Dial Transplant, 2017 Mar 25; 33(2). PMID: 28339906    Free PMC article.
Digital pathology imaging as a novel platform for standardization and globalization of quantitative nephropathology.
Laura Barisoni, Charlotte Gimpel, +8 authors, Stephen M Hewitt.
Clin Kidney J, 2017 Jun 07; 10(2). PMID: 28584625    Free PMC article.
Blood Pressure and Visit-to-Visit Blood Pressure Variability Among Individuals With Primary Proteinuric Glomerulopathies.
Christine B Sethna, Kevin E C Meyers, +6 authors, Tammy M Brady.
Hypertension, 2017 Jun 28; 70(2). PMID: 28652469    Free PMC article.
Renal biopsy-driven molecular target identification in glomerular disease.
Maja T Lindenmeyer, Matthias Kretzler.
Pflugers Arch, 2017 Jul 01; 469(7-8). PMID: 28664406
Digital pathology in nephrology clinical trials, research, and pathology practice.
Laura Barisoni, Jeffrey B Hodgin.
Curr Opin Nephrol Hypertens, 2017 Sep 01; 26(6). PMID: 28858910    Free PMC article.
Towards precision nephrology: the opportunities and challenges of genomic medicine.
Jordan G Nestor, Emily E Groopman, Ali G Gharavi.
J Nephrol, 2017 Oct 19; 31(1). PMID: 29043570    Free PMC article.
Reproducibility and Feasibility of Strategies for Morphologic Assessment of Renal Biopsies Using the Nephrotic Syndrome Study Network Digital Pathology Scoring System.
Jarcy Zee, Jeffrey B Hodgin, +8 authors, Laura Barisoni.
Arch Pathol Lab Med, 2018 Feb 20; 142(5). PMID: 29457738    Free PMC article.
A cross-sectional study on the relationship between hematological data and quantitative morphological indices from kidney biopsies in different glomerular diseases.
Michelangelo Nigro, Davide Viggiano, +6 authors, Giuseppe Gigliotti.
BMC Nephrol, 2018 Mar 16; 19(1). PMID: 29540159    Free PMC article.
Quantitative Large-Scale Three-Dimensional Imaging of Human Kidney Biopsies: A Bridge to Precision Medicine in Kidney Disease.
Seth Winfree, Pierre C Dagher, +6 authors, Tarek M El-Achkar.
Nephron, 2018 Jun 06; 140(2). PMID: 29870980    Free PMC article.
Deep Learning-Based Histopathologic Assessment of Kidney Tissue.
Meyke Hermsen, Thomas de Bel, +10 authors, Jeroen A W M van der Laak.
J Am Soc Nephrol, 2019 Sep 07; 30(10). PMID: 31488607    Free PMC article.
Renal SGLT mRNA expression in human health and disease: a study in two cohorts.
Vikas Srinivasan Sridhar, Jaya Prakash N Ambinathan, +7 authors, Nephrotic Syndrome Study Network (NEPTUNE).
Am J Physiol Renal Physiol, 2019 Sep 24; 317(5). PMID: 31545924    Free PMC article.
CureGN Study Rationale, Design, and Methods: Establishing a Large Prospective Observational Study of Glomerular Disease.
Laura H Mariani, Andrew S Bomback, +35 authors, CureGN Consortium.
Am J Kidney Dis, 2018 Nov 14; 73(2). PMID: 30420158    Free PMC article.
Urinary Epidermal Growth Factor as a Marker of Disease Progression in Children With Nephrotic Syndrome.
Debbie S Gipson, Howard Trachtman, +25 authors, Wenjun Ju.
Kidney Int Rep, 2020 Apr 14; 5(4). PMID: 32280839    Free PMC article.
Ultrastructural Characterization of Proteinuric Patients Predicts Clinical Outcomes.
Virginie Royal, Jarcy Zee, +9 authors, Laura Barisoni.
J Am Soc Nephrol, 2020 Feb 23; 31(4). PMID: 32086276    Free PMC article.
Hierarchical Clustering Analysis for Predicting 1-Year Mortality After Starting Hemodialysis.
Yohei Komaru, Teruhiko Yoshida, +2 authors, Kent Doi.
Kidney Int Rep, 2020 Aug 11; 5(8). PMID: 32775818    Free PMC article.
Estimated GFR Trajectories in Pediatric and Adult Nephrotic Syndrome: Results From the Nephrotic Syndrome Study Network (NEPTUNE).
Abigail R Smith, Jarcy Zee, +7 authors, Laura H Mariani.
Kidney Med, 2020 Aug 11; 2(4). PMID: 32775980    Free PMC article.
Digital pathology and computational image analysis in nephropathology.
Laura Barisoni, Kyle J Lafata, +2 authors, Ulysses G J Balis.
Nat Rev Nephrol, 2020 Aug 28; 16(11). PMID: 32848206    Free PMC article.
Estimating the Change in Renal Function During the First Year of Therapy in ANCA-Associated Vasculitis.
Fanny Lepeytre, Virginie Royal, +7 authors, Stéphan Troyanov.
Kidney Int Rep, 2019 Apr 18; 4(4). PMID: 30993234    Free PMC article.
Challenges in primary focal segmental glomerulosclerosis diagnosis: from the diagnostic algorithm to novel biomarkers.
Conxita Jacobs-Cachá, Ander Vergara, +7 authors, Maria José Soler.
Clin Kidney J, 2021 Feb 25; 14(2). PMID: 33623672    Free PMC article.
Incorporating longitudinal biomarkers for dynamic risk prediction in the era of big data: A pseudo-observation approach.
Lili Zhao, Susan Murray, Laura H Mariani, Wenjun Ju.
Stat Med, 2020 Jul 28; 39(26). PMID: 32717100    Free PMC article.
Nephrotic syndrome disease activity is proportional to its associated hypercoagulopathy.
Amanda P Waller, Jonathan P Troost, +7 authors, NEPTUNE Investigators.
Thromb Res, 2021 Feb 27; 201. PMID: 33636573    Free PMC article.
Sex and kidney ACE2 expression in primary focal segmental glomerulosclerosis: A NEPTUNE study.
Nicholas A Maksimowski, James W Scholey, Vanessa R Williams, Nephrotic Syndrome Study Network (NEPTUNE).
PLoS One, 2021 Jun 08; 16(6). PMID: 34097714    Free PMC article.
Dissecting the Business Case for Adoption and Implementation of Digital Pathology: A White Paper from the Digital Pathology Association.
Giovanni Lujan, Jennifer C Quigley, +16 authors, Doug Bowman.
J Pathol Inform, 2021 Jul 06; 12. PMID: 34221633    Free PMC article.
Kidney Injury Molecule-1 and Periostin Urinary Excretion and Tissue Expression Levels and Association with Glomerular Disease Outcomes.
Qiaoyan Wu, Jonathan P Troost, +9 authors, Sharon Adler.
Glomerular Dis, 2021 Aug 03; 1(2). PMID: 34337593    Free PMC article.
Assessment of a computerized quantitative quality control tool for whole slide images of kidney biopsies.
Yijiang Chen, Jarcy Zee, +11 authors, Andrew Janowczyk.
J Pathol, 2020 Nov 17; 253(3). PMID: 33197281    Free PMC article.
Development and evaluation of deep learning-based segmentation of histologic structures in the kidney cortex with multiple histologic stains.
Catherine P Jayapandian, Yijiang Chen, +12 authors, Nephrotic Syndrome Study Network (NEPTUNE).
Kidney Int, 2020 Aug 25; 99(1). PMID: 32835732    Free PMC article.
Follistatin-Like-1 (FSTL1) Is a Fibroblast-Derived Growth Factor That Contributes to Progression of Chronic Kidney Disease.
Nicholas A Maksimowski, Xuewen Song, +5 authors, Nephrotic Syndrome Study Network Neptune.
Int J Mol Sci, 2021 Sep 11; 22(17). PMID: 34502419    Free PMC article.
APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis.
Jarcy Zee, Michelle T McNulty, +45 authors, Matthew G Sampson.
Pediatr Nephrol, 2021 Mar 02; 36(9). PMID: 33646395    Free PMC article.
Machine Learning Applications in Nephrology: A Bibliometric Analysis Comparing Kidney Studies to Other Medicine Subspecialities.
Ashish Verma, Vipul C Chitalia, Sushrut S Waikar, Vijaya B Kolachalama.
Kidney Med, 2021 Oct 26; 3(5). PMID: 34693256    Free PMC article.