TY - JOUR
T1 - Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis
AU - Kidney Precision Medicine Project (KPMP)
AU - Schmidt, Insa M.
AU - Colona, Mia R.
AU - Kestenbaum, Bryan R.
AU - Alexopoulos, Leonidas G.
AU - Palsson, Ragnar
AU - Srivastava, Anand
AU - Liu, Jing
AU - Stillman, Isaac E.
AU - Rennke, Helmut G.
AU - Vaidya, Vishal S.
AU - Wu, Haojia
AU - Humphreys, Benjamin D.
AU - Waikar, Sushrut S.
AU - Knight, Richard
AU - Lecker, Stewart H.
AU - Stillman, Isaac
AU - Bogen, Steve
AU - Amodu, Afolarin A.
AU - Ilori, Titlayo
AU - Maikhor, Shana
AU - Beck, Laurence H.
AU - Henderson, Joel M.
AU - Onul, Ingrid
AU - Verma, Ashish
AU - McMahon, Gearoid M.
AU - Valerius, M. Todd
AU - Waikar, Sushrut
AU - Weins, Astrid
AU - Greka, Anna
AU - Hacohen, Nir
AU - Hoover, Paul J.
AU - Marshall, Jamie L.
AU - Aulisio, Mark
AU - Chen, Yijiang M.
AU - Janowczyk, Andrew
AU - Jayapandian, Catherine
AU - Viswanathan, Vidya S.
AU - Bush, William S.
AU - Crawford, Dana C.
AU - Madabhushi, Anant
AU - Bush, Lakeshia
AU - Cooperman, Leslie
AU - Gonzalez-Vicente, Agustin
AU - Herlitz, Leal
AU - Jolly, Stacey
AU - Nguyen, Jane
AU - O'toole, John
AU - Palmer, Ellen
AU - Poggio, Emilio
AU - Troyanskaya, Olga
N1 - Funding Information:
The authors thank the participants of the studies for their important contributions, and the study staff for their invaluable assistance. This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant U01DK104308 (to SSW and BDH) and National Institutes of Health (NIH) grant R01DK107931 and R01DK103986 (to BRK). The Kidney Precision Medicine Project, UG-DK-114907, is a multiyear project (see Supplementary Acknowledgments for consortium details) and is funded by the following grants from the NIDDK: U2C DK114886, UH3DK114861, UH3DK114866, UH3DK114870, UH3DK114908, UH3DK114915, UH3DK114926, UH3DK114907, UH3DK114920, UH3DK114923, UH3DK114933, and UH3DK114937. We are grateful to Kun Zhang ( University of California, San Diego ) and Sanjay Jain (Washington University) for providing unpublished snRNA-seq biopsy data supported by UH3DK114933. IMS is supported by the American Philosophical Society Daland Fellowship in Clinical Investigation. SSW is also supported by NIH grants UH3DK114915, U01DK085660, U01DK104308, R01DK103784, and R21DK119751. The Vaidya laboratory at Brigham and Women’s Hospital is supported by an Outstanding New Environmental Sciences (ONES) award from NIH/NIEHS (ES017543). AS is supported by NIH grant K23DK120811, NIDDK Kidney Precision Medicine Project Opportunity Pool grant under U2CDK114886, and core resources from the George M. O’Brien Kidney Research Center at Northwestern University (NU-GoKIDNEY) P30DK114857. LGA was co-financed by the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate (project code: 1EDK-03551). This work was conducted with support from Harvard Catalyst , the Harvard Clinical and Translational Science Center ( National Center for Advancing Translational Sciences, National Institutes of Health Award UL1TR001102 ), and financial contributions from Harvard University and its affiliated academic health care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University, and its affiliated academic health care centers, or the NIH. Part of this work was presented as a poster presentation at the 2020 American Society of Nephrology Scientific Session on October 22th. Funding for this work was provided by NIDDK grant U01DK104308 and NIH grants R01DK107931 and R01DK103986.
Funding Information:
The authors thank the participants of the studies for their important contributions, and the study staff for their invaluable assistance. This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant U01DK104308 (to SSW and BDH) and National Institutes of Health (NIH) grant R01DK107931 and R01DK103986 (to BRK). The Kidney Precision Medicine Project, UG-DK-114907, is a multiyear project (see Supplementary Acknowledgments for consortium details) and is funded by the following grants from the NIDDK: U2C DK114886, UH3DK114861, UH3DK114866, UH3DK114870, UH3DK114908, UH3DK114915, UH3DK114926, UH3DK114907, UH3DK114920, UH3DK114923, UH3DK114933, and UH3DK114937. We are grateful to Kun Zhang (University of California, San Diego) and Sanjay Jain (Washington University) for providing unpublished snRNA-seq biopsy data supported by UH3DK114933. IMS is supported by the American Philosophical Society Daland Fellowship in Clinical Investigation. SSW is also supported by NIH grants UH3DK114915, U01DK085660, U01DK104308, R01DK103784, and R21DK119751. The Vaidya laboratory at Brigham and Women's Hospital is supported by an Outstanding New Environmental Sciences (ONES) award from NIH/NIEHS (ES017543). AS is supported by NIH grant K23DK120811, NIDDK Kidney Precision Medicine Project Opportunity Pool grant under U2CDK114886, and core resources from the George M. O'Brien Kidney Research Center at Northwestern University (NU-GoKIDNEY) P30DK114857. LGA was co-financed by the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call Research-Create-Innovate (project code: 1EDK-03551). This work was conducted with support from Harvard Catalyst, the Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL1TR001102), and financial contributions from Harvard University and its affiliated academic health care centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University, and its affiliated academic health care centers, or the NIH. Part of this work was presented as a poster presentation at the 2020 American Society of Nephrology Scientific Session on October 22th. Funding for this work was provided by NIDDK grant U01DK104308 and NIH grants R01DK107931 and R01DK103986. IMS and SSW were responsible for the concept and design of the study. MRC, AS, RP, BRK, and VSV made important contributions to data collection, acquisition, and analysis. IES and HGR were responsible for the adjudication of histopathology. HW and BDH were responsible for scRNA-sequencing and snRNA-sequencing data analyses. LGA measured the plasma biomarkers. IMS, JL, and SSW were responsible for the statistical analysis. All authors interpreted the data. IMS and SSW drafted the manuscript. All authors contributed to critical revisions of the manuscript for important intellectual content.
Publisher Copyright:
© 2021 International Society of Nephrology
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
KW - biomarker
KW - biopsy
KW - fibrosis
KW - histopathology
KW - kidney disease
UR - http://www.scopus.com/inward/record.url?scp=85110412207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85110412207&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2021.04.037
DO - 10.1016/j.kint.2021.04.037
M3 - Article
C2 - 34051265
AN - SCOPUS:85110412207
SN - 0085-2538
VL - 100
SP - 672
EP - 683
JO - Kidney International
JF - Kidney International
IS - 3
ER -