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1. Integrated single-cell sequencing and histopathological analyses reveal diverse injury and repair responses in a participant with acute kidney injury: a clinical-molecular-pathologic correlation

Author

Rajasree Menon, Andrew S. Bomback, Blue B. Lake, Christy Stutzke, Stephanie M. Grewenow, Steven Menez, Vivette D. D’Agati, Sanjay Jain, Richard Knight, Stewart H. Lecker, Isaac Stillman, Steve Bogen, Laurence H. Beck, Sushrut Waikar, Gearoid M. McMahon, Astrid Weins, Mia R. Colona, Nir Hacohen, Paul J. Hoover, Mark Aulisio, William S. Bush, Dana C. Crawford, John O'toole, Emilio Poggio, John Sedor, Leslie Cooperman, Stacey Jolly, Leal Herlitz, Jane Nguyen, Agustin Gonzalez-Vicente, Ellen Palmer, Dianna Sendrey, Carissa Vinovskis, Petter M. Bjornstad, Paul Appelbaum, Jonathan M. Barasch, Vivette D. D'Agati, Krzysztof Kiryluk, Karla Mehl, Pietro A. Canetta, Ning Shang, Olivia Balderes, Satoru Kudose, Shweta Bansal, Theodore Alexandrov, Helmut Rennke, Tarek M. El-Achkar, Yinghua Cheng, Pierre C. Dagher, Michael T. Eadon, Kenneth W. Dunn, Katherine J. Kelly, Timothy A. Sutton, Daria Barwinska, Michael J. Ferkowicz, Seth Winfree, Sharon Bledsoe, Marcelino Rivera, James C. Williams, Ricardo Melo Ferreira, Chirag R. Parikh, Celia P. Corona-Villalobos, Avi Rosenberg, Sylvia E. Rosas, Neil Roy, Mark Williams, Evren U. Azeloglu, Cijang He, Ravi Iyengar, Jens Hansen, Yuguang Xiong, Brad Rovin, Samir Parikh, John P. Shapiro, Christopher R. Anderton, Ljiljana Pasa-Tolic, Dusan Velickovic, Jessica Lukowski, George Oliver, Joseph Ardayfio, Jack Bebiak, Keith Brown, Catherine E. Campbell, John Saul, Anna Shpigel, Robert Koewler, Taneisha Campbell, Lynda Hayashi, Nichole Jefferson, Glenda V. Roberts, Roy Pinkeney, Olga Troyanskaya, Rachel Sealfon, Katherine R. Tuttle, Yury Goltsev, Kun Zhang, Zoltan G. Laszik, Garry Nolan, Patrick Boada, Minnie Sarwal, Tara Sigdel, Paul J. Lee, Rita R. Alloway, E. Steve Woodle, Heather Ascani, Ulysses G.J. Balis, Jeffrey B. Hodgin, Matthias Kretzler, Chrysta Lienczewski, Laura H. Mariani, Becky Steck, Yougqun He, Edgar Otto, Jennifer Schaub, Victoria M. Blanc, Sean Eddy, Ninive C. Conser, Jinghui Luo, Paul M. Palevsky, Matthew Rosengart, John A. Kellum, Daniel E. Hall, Parmjeet Randhawa, Mitchell Tublin, Raghavan Murugan, Michele M. Elder, James Winters, Charles E. Alpers, Kristina N. Blank, Jonas Carson, Ian H. De Boer, Ashveena L. Dighe, Jonathan Himmelfarb, Sean D. Mooney, Stuart Shankland, Kayleen Williams, Christopher Park, Frederick Dowd, Robyn L. McClelland, Stephen Daniel, Andrew N. Hoofnagle, Adam Wilcox, Kumar Sharma, Manjeri Venkatachalam, Guanshi Zhang, Annapurna Pamreddy, Hongping Ye, Richard Montellano, Robert D. Toto, Miguel Vazquez, Simon C. Lee, R. Tyler Miller, Orson W. Moe, Jose Torrealba, Nancy Wang, Asra Kermani, Kamalanathan Sambandam, Harold Park, S. Susan Hedayati, Christopher Y. Lu, Anitha Vijayan, Joseph P. Gaut, Dennis Moledina, Francis P. Wilson, Ugochukwu Ugwuowo, and Tanima Arora

Subjects
Pathology, Clinical, Nephrology, Humans, Acute Kidney Injury, Kidney, Article
Published
2022

2. Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis

Author

Mark E. Williams, Katherine R. Tuttle, Jing Liu, Jinghui Luo, Yougqun He, Laura Pyle, Blue B. Lake, Brad H. Rovin, Lynda Hayashi, Yuguang Xiong, Dennis G. Moledina, Andreas Bueckle, Steven Menez, Glenda V. Roberts, Anand Srivastava, Paul Appelbaum, Heather Ascani, Catherine Campbell, Stephanie M. Grewenow, Mark Aulisio, Jennifer Sun, Christopher R. Anderton, Jamie L. Marshall, Sharon Bledso, John P. Shapiro, Theodore Alexandrov, Richard M. Caprioli, Michele Elder, Leslie Cooperman, Shweta Bansal, Lakeshia Bush, Krzysztof Kiryluk, Mitchell Tublin, Olga G. Troyanskaya, Emilio D. Poggio, Kristina N. Blank, Andrew Janowczyk, Paul Hoover, Sabine M. Diettman, R. Tyler Miller, Katy Borner, Leonidas G. Alexopoulos, James Winters, Anant Madabhushi, Haojia Wu, Chirag R. Parikh, Yumeng Wen, Avi Z. Rosenberg, Agustin Gonzalez-Vicente, Leal Herlitz, Keith Brown, Matthew Gilliam, Joseph P. Gaut, Vidya S. Viswanathan, Karla Mehl, Stewart H. Lecker, Pierre C. Dagher, Dana C. Crawford, Camille Johansen, Anna Greka, Tiffany Shi, Ari Pollack, Renee Frey, Kavya Sharman, Isaac E. Stillman, Stuart J. Shankland, Ricardo Melo Ferreira, Jack Bebiak, Jing Su, Matthias Kretzler, Ellen Palmer, Yury Goltsev, Aaron K. Wong, Matthew R. Rosengart, Taneisha Campbell, Tina Vita, Helmut G. Rennke, Nir Hacohen, Satoru Kudose, Christine Limonte, Kun Zhang, Robyn L. McClelland, Ulysses J. Balis, Katherine J. Kelly, Simon Lee, Ninive C. Conser, Adele Rike, Frederick Dowd, Timothy A. Sutton, Steve Bogen, Petter M. Bjornstad, Zoltan Laszik, Dianbo Zhang, Benjamin D. Humphreys, Pinaki Sarder, Jeffrey M. Spraggins, Ravi Iyengar, Marcelino Rivera, Roy Pinkeney, James C. Williams, Tarek M. El-Achkar, Laura H. Mariani, Richard J. Knight, Manjeri A. Venkatachalam, Pietro A. Canetta, Lloyd G. Cantley, Kayleen Williams, Catherine P. Jayapandian, Edgar A. Otto, Jessica Lukowski, Kassandra Spates-Harden, Ashish Verma, John Saul, Tariq Mukatash, Mia R. Colona, Shana Maikhor, Laurence H. Beck, Titlayo Ilori, Charles E. Alpers, Ellen M. Quardokus, Mujeeb Basit, Dušan Veličković, Raf Van de Plas, Jonathan Himmelfarb, Michael T. Eadon, Chrysta Lienczewski, Christopher Y. Lu, Yijiang M. Chen, Kasra Rezaei, Richard Montellano, Pottumarthi V. Prasad, Francis P. Wilson, Christy Stutzke, Jane Nguyen, Kamalanathan K. Sambandam, Miguel A. Vazquez, Vishal S. Vaidya, Vivette D. D'Agati, Patrick Boada, Adam Wilcox, Astrid Weins, Jennifer A. Schaub, Harold Park, Kumar Sharma, M. Todd Valerius, Stephen Daniel, Sean Eddy, Bruce W. Herr, Kenneth W. Dunn, Jamie Snyder, E. Steve Woodle, Dianna Sendrey, Ljiljana Paša-Tolić, Raghavan Murugan, Brandon Ginley, Bryan Kestenbaum, Celia P. Corona-Villalobos, Olivia Balderes, Sushrut Waikar, Carissa Vinovskis, Brooke Berry, Parmjeet Randhawa, Seth Winfree, Jose R. Torrealba, Ning Shang, Rachel Sealfon, Michael J. Ferkowicz, William S. Bush, Jonas Carson, Robert Koewler, Guanshi Zhang, Robert D. Toto, Ian H. de Boer, Gearoid M. McMahon, Andrew N. Hoofnagle, Vijaykumar R. Kakade, Brendon Lutnick, Melissa M. Shaw, Rita R. Alloway, Rajasree Menon, Afolarin Amodu, Jeanine Basta, Paul J. Lee, Ingrid Onul, Sylvia E. Rosas, Cijang (John) He, Andrew S. Bomback, Yinghua Cheng, Jeffrey B. Hodgin, Samir M. Parikh, Garry Nolan, John A. Kellum, Anil Pillai, Annapurna Pamreddy, Orson W. Moe, Jiten Patel, Jonathan J. Taliercio, S. Susan Hedayati, Anitha Vijayan, Tanima Arora, Evren U. Azeloglu, Paul M. Palevsky, Nathan Heath Patterson, Asra Kermani, Becky Steck, Kavya Anjani, Ashley Berglund, Yashvardhan Jain, Stacey E. Jolly, John R. Sedor, George (Holt) Oliver, Natasha Wen, Nancy Wang, Ruikang Wang, Joseph Ardayfio, Michael Rauchman, Ashley R. Burg, Victoria Blanc, Minnie M. Sarwal, Daniel Hall, Sethu M. Madhavan, Sean D. Mooney, Sushrut S. Waikar, Daria Barwinska, Christopher Y. Park, Tara K. Sigdel, Ugochukwu Ugwuowo, John F. O'Toole, Ragnar Palsson, Insa M. Schmidt, Joel M. Henderson, Hongping Ye, Jens Hansen, Jonathan Barasch, Neil Roy, Nicholas Lucarelli, Anna Shpigel, Ashveena Dighe, Elizabeth Record, Sanjay Jain, and Nichole Jefferson

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Urinary system, 030232 urology & nephrology, Kidney, Article, 03 medical and health sciences, 0302 clinical medicine, PEDF, Fibrosis, Biopsy, Humans, Medicine, Osteonectin, Nerve Growth Factors, Prospective Studies, Renal Insufficiency, Chronic, Eye Proteins, Serpins, medicine.diagnostic_test, urogenital system, business.industry, Calcium-Binding Proteins, Cadherins, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Nephrology, Cohort, Disease Progression, Biomarker (medicine), business, Biomarkers, Kidney disease
Abstract

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

Published
2021

3. A Participant-Centered Approach to Understanding Risks and Benefits of Participation in Research Informed by the Kidney Precision Medicine Project

Author

Catherine R. Butler, Paul S. Appelbaum, Heather Ascani, Mark Aulisio, Catherine E. Campbell, Ian H. de Boer, Ashveena L. Dighe, Daniel E. Hall, Jonathan Himmelfarb, Richard Knight, Karla Mehl, Raghavan Murugan, Sylvia E. Rosas, John R. Sedor, John F. O’Toole, Katherine R. Tuttle, Sushrut S. Waikar, Michael Freeman, Theodore Alexandrov, Charles E. Alpers, Christopher R. Anderton, Joseph Ardayfio, Tanima Arora, Tarek M. El-Achkar, Evren U. Azeloglu, Olivia Balderes, Ulysses G.J. Balis, Shweta Bansal, Jonathan M. Barasch, Daria Barwinska, Jack Bebiak, Victoria M. Blanc, Kristina N. Blank, Andrew S. Bomback, Keith D. Brown, William S. Bush, Taneisha Campbell, Pietro A. Canetta, Jonas Carson, Leslie Cooperman, Dana C. Crawford, Vivette D. D’Agati, Pierre C. Dagher, Stephen Daniel, Frederick Dowd, Kenneth W. Dunn, Michael T. Eadon, Sean Eddy, Michele M. Elder, Michael J. Ferkowicz, Joe P. Gaut, Yury Goltsev, Agustin Gonzalez-Vicente, Nir Hacohen, Jens Hansen, Lynda Hayashi, Oliver He, Cijang He, S. Susan Hedayati, Leal Herlitz, Jeffrey B. Hodgin, Andrew N. Hoofnagle, Paul J. Hoover, Ravi Iyengar, Sanjay Jain, Nichole Jefferson, Stacey Jolly, John A. Kellum, Katherine J. Kelly, Asra Kermani, Krzysztof Kiryluk, Robert Koewler, Matthias Kretzler, Blue B. Lake, Zoltan G. Laszik, Stewart H. Lecker, Simon C. Lee, Chrysta Lienczewski, Christopher Y. Lu, Laura H. Mariani, Robyn L. McClelland, Gearoid M. McMahon, Steven Menez, Rajasree Menon, Tyler Miller, Orson W. Moe, Dennis Moledina, Sean D. Mooney, Jane Nguyen, Garry Nolan, George Oliver, Edgar Otto, Paul M. Palevsky, Ellen Palmer, Annapurna Pamreddy, Chirag R. Parikh, Samir Parikh, Christopher Park, Harold Park, Ljiljana Pasa-Tolic, Roy Pinkeney, Emilio Poggio, Parmjeet Randhawa, Helmut Rennke, Glenda V. Roberts, Avi Rosenberg, Matthew Rosengart, Brad Rovin, Neil Roy, Kamalanathan Sambandam, Minnie Sarwal, John Saul, Jennifer Schaub, Rachel Sealfon, Ning Shang, Stuart Shankland, Kumar Sharma, Anna Shpigel, Tara Sigdel, Becky Steck, Isaac Stillman, Edith Christine Stutzke, Timothy A. Sutton, Jose Torrealba, Robert D. Toto, Olga Troyanskaya, Mitchell Tublin, Ugochukwu Ugwuowo, Miguel Vazquez, Dusan Velickovic, Manjeri Venkatachalam, Anitha Vijayan, Celia P. Corona-Villalobos, Nancy Wang, Astrid Weins, Adam Wilcox, Kayleen Williams, Mark Williams, Francis P. Wilson, Seth Winfree, Yuguang Xiong, Kun Zhang, and Guanshi Zhang

Subjects
Informed Consent, Nephrology, Humans, Precision Medicine, Kidney, Risk Assessment, Article, Research Personnel
Abstract

An understanding of the ethical underpinnings of human subjects research that involves some risk to participants without anticipated direct clinical benefit-such as the kidney biopsy procedure as part of the Kidney Precision Medicine Project (KPMP)-requires a critical examination of the risks as well as the diverse set of countervailing potential benefits to participants. This kind of deliberation has been foundational to the development and conduct of the KPMP. Herein, we use illustrative features of this research paradigm to develop a more comprehensive conceptualization of the types of benefits that may be important to research participants, including respecting pluralistic values, supporting the opportunity to act altruistically, and enhancing benefits to a participant's community. This approach may serve as a model to help researchers, ethicists, and regulators to identify opportunities to better respect and support participants in future research that entails some risk to these participants as well as to improve the quality of research for people with kidney disease.

Published
2021

4. Rationale and design of the Kidney Precision Medicine Project

Author

Ian H. de Boer, Charles E. Alpers, Evren U. Azeloglu, Ulysses G.J. Balis, Jonathan M. Barasch, Laura Barisoni, Kristina N. Blank, Andrew S. Bomback, Keith Brown, Pierre C. Dagher, Ashveena L. Dighe, Michael T. Eadon, Tarek M. El-Achkar, Joseph P. Gaut, Nir Hacohen, Yongqun He, Jeffrey B. Hodgin, Sanjay Jain, John A. Kellum, Krzysztof Kiryluk, Richard Knight, Zoltan G. Laszik, Chrysta Lienczewski, Laura H. Mariani, Robyn L. McClelland, Steven Menez, Dennis G. Moledina, Sean D. Mooney, John F. O’Toole, Paul M. Palevsky, Chirag R. Parikh, Emilio D. Poggio, Sylvia E. Rosas, Matthew R. Rosengart, Minnie M. Sarwal, Jennifer A. Schaub, John R. Sedor, Kumar Sharma, Becky Steck, Robert D. Toto, Olga G. Troyanskaya, Katherine R. Tuttle, Miguel A. Vazquez, Sushrut S. Waikar, Kayleen Williams, Francis Perry Wilson, Kun Zhang, Ravi Iyengar, Matthias Kretzler, Jonathan Himmelfarb, Stewart Lecker, Isaac Stillman, Sushrut Waikar, Gearoid Mcmahon, Astrid Weins, Samuel Short, Paul Hoover, Mark Aulisio, Leslie Cooperman, Leal Herlitz, John O’Toole, Emilio Poggio, John Sedor, Stacey Jolly, Paul Appelbaum, Olivia Balderes, Jonathan Barasch, Andrew Bomback, Pietro A. Canetta, Vivette D. d’Agati, Satoru Kudose, Karla Mehl, Jai Radhakrishnan, Chenhua Weng, Theodore Alexandrov, Tarek Ashkar, Daria Barwinska, Pierre Dagher, Kenneth Dunn, Michael Eadon, Michael Ferkowicz, Katherine Kelly, Timothy Sutton, Seth Winfree, Chirag Parikh, Avi Rosenberg, Pam Villalobos, Rubab Malik, Derek Fine, Mohammed Atta, Jose Manuel Monroy Trujillo, Alison Slack, Sylvia Rosas, Mark Williams, Evren Azeloglu, Cijang (John) He, Jens Hansen, Samir Parikh, Brad Rovin, Chris Anderton, Ljiljana Pasa-Tolic, Dusan Velickovic, Jessica Lukowski, George (Holt) Oliver, Joseph Ardayfio, Jack Bebiak, Taneisha Campbell, Catherine Campbell, Lynda Hayashi, Nichole Jefferson, Robert Koewler, Glenda Roberts, John Saul, Anna Shpigel, Edith Christine Stutzke, Lorenda Wright, Leslie Miegs, Roy Pinkeney, Rachel Sealfon, Olga Troyanskaya, Katherine Tuttle, Dejan Dobi, Yury Goltsev, Blue Lake, Maria Joanes, Zoltan Laszik, Andrew Schroeder, Minnie Sarwal, Tara Sigdel, Ulysses Balis, Victoria Blanc, Oliver He, Jeffrey Hodgin, Laura Mariani, Rajasree Menon, Edgar Otto, Jennifer Schaub, Sean Eddy, Michele Elder, Daniel Hall, John Kellum, Mary Kruth, Raghav Murugan, Paul Palevsky, Parmjeet Randhawa, Matthew Rosengart, Sunny Sims-Lucas, Mary Stefanick, Stacy Stull, Mitchell Tublin, Charles Alpers, Ian de Boer, Ashveena Dighe, Robyn Mcclelland, Sean Mooney, Stuart Shankland, Kristina Blank, Jonas Carson, Frederick Dowd, Zach Drager, Christopher Park, Guanshi Zhang, Shweta Bansal, Manjeri Venkatachalam, Asra Kermani, Simon Lee, Christopher Lu, Tyler Miller, Orson Moe, Harold Park, Kamalanathan Sambandam, Francisco Sanchez, Jose Torrealba, Toto Robert, Miguel Vazquez, Nancy Wang, Joe Gaut, Anitha Vijayan, Randy Luciano, Dennis Moledina, Ugwuowo Ugochukwu, and Sandy Alfano

Subjects
0301 basic medicine, Adult, Proteomics, medicine.medical_specialty, 030232 urology & nephrology, Subgroup analysis, Disease, urologic and male genital diseases, Kidney, Article, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, medicine, Humans, Prospective Studies, Precision Medicine, Renal Insufficiency, Chronic, Intensive care medicine, Prospective cohort study, business.industry, urogenital system, Acute kidney injury, Acute Kidney Injury, Precision medicine, medicine.disease, female genital diseases and pregnancy complications, 030104 developmental biology, medicine.anatomical_structure, Nephrology, business, Kidney disease
Abstract

Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living kidney donor biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomics analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for ten years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.

Published
2021

5. Large-scale, three-dimensional tissue cytometry of the human kidney: a complete and accessible pipeline

Author

Michael J. Ferkowicz, Seth Winfree, Angela R. Sabo, Malgorzata M. Kamocka, Suraj Khochare, Daria Barwinska, Michael T. Eadon, Ying-Hua Cheng, Carrie L. Phillips, Timothy A. Sutton, Katherine J. Kelly, Pierre C. Dagher, Tarek M. El-Achkar, Kenneth W. Dunn, Richard Knight, Stewart Lecker, Isaac Stillman, Gearoid Mcmahon, Sus Waikar, Astrid Weins, Nir Hacohen, Paul Hoover, Mark Aulisio, Leslie Cooperman, Leal Herlitz, John O'toole, Emilio Poggio, John Sedor, Paul Appelbaum, Jonathan Barasch, Andrew Bomback, Vivette D'agati, Krzysztof Kiryluk, Karla Mehl, Ning (Sunny) Shang, Chenhua Weng, Laura Barisoni, Theodore Alexandrov, Tarek Ashkar, Pierre Dagher, Kenneth Dunn, Michael Eadon, Michael Ferkowicz, Katherine Kelly, Timothy Sutton, Steven Menez, Chirag Parikh, Avi Rosenberg, Pam Villalobos, Alison Slack, Sylvia Rosas, Mark Williams, Evren Azeloglu, Cijang (John) He, Ravi Iyengar, Samir Parikh, Chris Anderton, Ljiljana Pasa-Tolic, Dusan Velickovic, George (Holt) Oliver, Joseph Ardayfio, Jack Bebiak, Keith Brown, Taneisha Campbell, Catherine Campbell, Lynda Hayashi, Nichole Jefferson, Robert Koewler, Glenda Roberts, John Saul, Anna Shpigel, Edith Christine Stutzke, Lorenda Wright, Leslie Miegs, Roy Pinkeney, Rachel Sealfon, Olga Troyanskaya, Katherine Tuttle, Yury Goltsev, Blue Lake, Kun Zhang, Dejan Dobi, Maria Joanes, Zoltan Laszik, Garry Nolan, Andrew Schroeder, Ulysses Balis, Oliver He, Jeffrey Hodgin, Matthias Kretzler, Laura Mariani, Rajasree Menon, Edgar Otto, Jennifer Schaub, Becky Steck, Michele Elder, Daniel Hall, John Kellum, Mary Kruth, Raghav Murugan, Paul Palevsky, Parmjeet Randhawa, Matthew Rosengart, Sunny Sims-Lucas, Mary Stefanick, Stacy Stull, Mitchell Tublin, Charles Alpers, Ian De Boer, Malia Fullerton, Jonathan Himmelfarb, Robyn Mcclelland, Sean Mooney, Stuart Shankland, Kayleen Williams, Kristina Blank, Ashveena Dighe, Jonas Carson, Frederick Dowd, Zach Drager, Kumar Sharma, Guanshi Zhang, Asra Kermani, Simon Lee, Christopher Lu, Tyler Miller, Orson Moe, Harold Park, Kamalanathan Sambandam, Francisco Sanchez, Jose Torrealba, Toto Robert, Miguel Vazquez, Nancy Wang, Joe Gaut, Sanjay Jain, Anitha Vijayan, Randy Luciano, Dennis Moledina, Ugwuowo Ugochukwu, and Francis Perry Wilson

Subjects
0301 basic medicine, Computer science, Confocal, Cytological Techniques, Context (language use), Kidney, Article, Pathology and Forensic Medicine, law.invention, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Imaging, Three-Dimensional, Confocal microscopy, law, Microscopy, medicine, Humans, Image analysis, Molecular Biology, Fluorescent Dyes, Microscopy, Confocal, medicine.diagnostic_test, Cell Biology, Autofluorescence, 030104 developmental biology, Microscopy, Fluorescence, Multiphoton, 030220 oncology & carcinogenesis, Cytometry, Software, Biomedical engineering
Abstract

The advent of personalized medicine has driven the development of novel approaches for obtaining detailed cellular and molecular information from clinical tissue samples. Tissue cytometry is a promising new technique that can be used to enumerate and characterize each cell in a tissue and, unlike flow cytometry and other single-cell techniques, does so in the context of the intact tissue, preserving spatial information that is frequently crucial to understanding a cell’s physiology, function, and behavior. However, the wide-scale adoption of tissue cytometry as a research tool has been limited by the fact that published examples utilize specialized techniques that are beyond the capabilities of most laboratories. Here we describe a complete and accessible pipeline, including methods of sample preparation, microscopy, image analysis, and data analysis for large-scale three-dimensional tissue cytometry of human kidney tissues. In this workflow, multiphoton microscopy of unlabeled tissue is first conducted to collect autofluorescence and second-harmonic images. The tissue is then labeled with eight fluorescent probes, and imaged using spectral confocal microscopy. The raw 16-channel images are spectrally deconvolved into 8-channel images, and analyzed using the Volumetric Tissue Exploration and Analysis (VTEA) software developed by our group. We applied this workflow to analyze millimeter-scale tissue samples obtained from human nephrectomies and from renal biopsies from individuals diagnosed with diabetic nephropathy, generating a quantitative census of tens of thousands of cells in each. Such analyses can provide useful insights that can be linked to the biology or pathology of kidney disease. The approach utilizes common laboratory techniques, is compatible with most commercially-available confocal microscope systems and all image and data analysis is conducted using the VTEA image analysis software, which is available as a plug-in for ImageJ. Tissue cytometry is a promising new microscopy technique that can be used to enumerate and characterize each cell in a tissue. Here the authors describe a complete and accessible pipeline, including methods of sample preparation, microscopy, image analysis, and data analysis for large-scale three-dimensional tissue cytometry of human kidney tissues.

Published
2020

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