@article{e8b19f4b6f054ea199199d685302a3c8,
title = "Single cell transcriptomics identifies focal segmental glomerulosclerosis remission endothelial biomarker",
abstract = "To define cellular mechanisms underlying kidney function and failure, the KPMP analyzes biopsy tissue in a multicenter research network to build cell-level process maps of the kidney. This study aimed to establish a single cell RNA sequencing strategy to use cell-level transcriptional profiles from kidney biopsies in KPMP to define molecular subtypes in glomerular diseases. Using multiple sources of adult human kidney reference tissue samples, 22,268 single cell profiles passed KPMP quality control parameters. Unbiased clustering resulted in 31 distinct cell clusters that were linked to kidney and immune cell types using specific cell markers. Focusing on endothelial cell phenotypes, in silico and in situ hybridization methods assigned 3 discrete endothelial cell clusters to distinct renal vascular beds. Transcripts defining glomerular endothelial cells (GEC) were evaluated in biopsies from patients with 10 different glomerular diseases in the NEPTUNE and European Renal cDNA Bank (ERCB) cohort studies. Highest GEC scores were observed in patients with focal segmental glomerulosclerosis (FSGS). Molecular endothelial signatures suggested 2 distinct FSGS patient subgroups with α-2 macroglobulin (A2M) as a key downstream mediator of the endothelial cell phenotype. Finally, glomerular A2M transcript levels associated with lower proteinuria remission rates, linking endothelial function with long-term outcome in FSGS.",
author = "{Kidney Precision Medicine Project (KPMP),5 and Nephrotic Syndrome Study Network (NEPTUNE)} and Rajasree Menon and Otto, {Edgar A.} and Paul Hoover and Sean Eddy and Laura Mariani and Bradley Godfrey and Berthier, {Celine C.} and Felix Eichinger and Lalita Subramanian and Jennifer Harder and Wenjun Ju and Viji Nair and Maria Larkina and Naik, {Abhijit S.} and Jinghui Luo and Sanjay Jain and Rachel Sealfon and Olga Troyanskaya and Nir Hacohen and Hodgin, {Jeffrey B.} and Matthias Kretzler",
note = "Funding Information: the advisory boards of JDRF, Astra- Zeneca, NovoNordisc, Eli Lilly, Gilead, Goldfinch Bio, Merck, Chan Zuckerberg Initiative, Janssen, Boehringer-Ingelheim, Elpidera, European Union Innovative Medicine Initiative. MK and WJ hold a patent Biomarkers for CKD progression (encompassing urinary EGF as biomarker of CKD progression). OT serves on the Scientific Advisory Boards of Caris Life Sciences and Goldfinch Bio; OT served on Scientific Advisory Boards, received grants or honoraria from UBC, Google, and Renaissance Technologies LLC. LM reports grant funding from Boehringer-Ingelheim and serves as an advisory board member for Reata Pharmaceuticals. WJ has received support for diabetic kidney disease–associated research from the Joint Institute for Translational and Clinical Research (PUUMA). CCB has received support for IgA nephropathy-associated research from the Joint Institute for Translational and Clinical Research (PUUMA). JBH reports grants from Astra-Zeneca, Gilead, and Moderna. Funding Information: KPMP, UG-DK-114907, is a multiyear project funded by the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) with the purpose of understanding and finding new ways to treat chronic kidney disease and acute kidney injury. See Supplemental Acknowledgments for consortium details. The NEPTUNE consortium, U54-DK-083912, is a part of the NIH Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, and the NIDDK. See Supplemental Acknowledgments for consortium details. ERCB members at the time of the study: Clemens David Cohen, Holger Schmid, Michael Fischereder, and Lutz Weber (Munich, Germany); Matthias Kretzler (Ann Arbor, Michigan, USA); Detlef Schl{\"o}ndorff (New York, New York, USA); Jean Daniel Sraer and Pierre Ronco (Paris, France); Maria Pia Rastaldi and Giuseppe D{\textquoteright}Amico (Milano, Italy); Peter Doran and Hugh Brady (Dublin, Ireland); Detlev M{\"o}nks and Christoph Wanner (W{\"u}rzburg, Germany); Andrew Rees (Vienna, Austria); Frank Strutz and Gerhard Anton M{\"u}ller (G{\"o}ttingen, Germany); Peter Mertens and J{\"u}rgen Floege (Aachen, Germany); Norbert Braun and Teut Risler (T{\"u}bingen, Germany); Loreto Gesualdo and Francesco Paolo Schena (Bari, Italy); Gunter Wolf (Jena, Germany); Rainer Oberbauer and Dontscho Kerjaschki (Vienna, Austria); Bernhard Banas and Bernhard Kr{\"a}mer (Regensburg, Germany); Moin Saleem (Bristol, United Kingdom); Rudolf W{\"u}thrich (Zurich, Switzerland); Walter Samtleben (Munich, Germany); Harm Peters and Hans-Hellmut Neumayer (Berlin, Germany); Mohamed Daha (Leiden, Netherlands); Katrin Ivens and Bernd Grabensee (D{\"u}sseldorf, Germany); Francisco Mampaso (Madrid, Spain); Jun Oh, Franz Schae-fer, Martin Zeier, and Hermann-Joseph Gr{\"o}ne (Heidelberg, Germany); Peter Gross (Dresden, Germany); Giancarlo Tonolo (Sassari, Italy); Vladimir Tesar (Prague, Czech Republic); Harald Rupprecht (Bayreuth, Germany); Hermann Pavenst{\"a}dt (M{\"u}nster, Germany); Hans-Peter Marti (Bern, Switzerland); Peter Mer-tens (Magdeburg, Germany); and Jens Gerth (Zwickau, Germany). Funding Information: KPMP, UG-DK-114907, is a multiyear project funded by the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) with the purpose of understanding and finding new ways to treat chronic kidney disease and acute kidney injury. See Supplemental Acknowledgments for consortium details. The NEPTUNE consortium, U54-DK-083912, is a part of the NIH Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, and the NIDDK. See Supplemental Acknowledgments for consortium details. ERCB members at the time of the study: Clemens David Cohen, Holger Schmid, Michael Fischereder, and Lutz Weber (Munich, Germany); Matthias Kretzler (Ann Arbor, Michigan, USA); Detlef Schl{\"o}ndorff (New York, New York, USA); Jean Daniel Sraer and Pierre Ronco (Paris, France); Maria Pia Rastaldi and Giuseppe D'Amico (Milano, Italy); Peter Doran and Hugh Brady (Dublin, Ireland); Detlev M{\"o}nks and Christoph Wanner (W{\"u}rzburg, Germany); Andrew Rees (Vienna, Austria); Frank Strutz and Gerhard Anton M{\"u}ller (G{\"o}ttingen, Germany); Peter Mertens and J{\"u}rgen Floege (Aachen, Germany); Norbert Braun and Teut Risler (T{\"u}bingen, Germany); Loreto Gesualdo and Francesco Paolo Schena (Bari, Italy); Gunter Wolf (Jena, Germany); Rainer Oberbauer and Dontscho Kerjaschki (Vienna, Austria); Bernhard Banas and Bernhard Kr{\"a}mer (Regensburg, Germany); Moin Saleem (Bristol, United Kingdom); Rudolf W{\"u}thrich (Zurich, Switzerland); Walter Samtleben (Munich, Germany); Harm Peters and Hans-Hellmut Neumayer (Berlin, Germany); Mohamed Daha (Leiden, Netherlands); Katrin Ivens and Bernd Grabensee (D{\"u}sseldorf, Germany); Francisco Mampaso (Madrid, Spain); Jun Oh, Franz Schaefer, Martin Zeier, and Hermann-Joseph Gr{\"o}ne (Heidelberg, Germany); Peter Gross (Dresden, Germany); Giancarlo Tonolo (Sassari, Italy); Vladimir Tesar (Prague, Czech Republic); Harald Rupprecht (Bayreuth, Germany); Hermann Pavenst{\"a}dt (M{\"u}nster, Germany); Hans-Peter Marti (Bern, Switzerland); Peter Mertens (Magdeburg, Germany); and Jens Gerth (Zwickau, Germany). We thank Thomas Giordano and Daffyd Thomas, University of Michigan Tissue Procurement Service, for providing us with deidentified human kidney tissue in FFPE blocks and Yingbao Yang for the PAS staining of slides for the ISH data. This study was supported, in part, by the George M. O'Brien Michigan Kidney Translational Core Center, funded by NIH/NIDDK grant 2P30-DK-081943. Funding Information: We thank Thomas Giordano and Daffyd Thomas, University of Michigan Tissue Procurement Service, for providing us with deidentified human kidney tissue in FFPE blocks and Yingbao Yang for the PAS staining of slides for the ISH data. This study was supported, in part, by the George M. O{\textquoteright}Brien Michigan Kidney Translational Core Center, funded by NIH/NIDDK grant 2P30-DK-081943. Publisher Copyright: Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",
year = "2020",
month = mar,
day = "26",
doi = "10.1172/jci.insight.133267",
language = "English (US)",
volume = "5",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "6",
}