Elastin imaging enables noninvasive staging and treatment monitoring of kidney fibrosis

Qinxue Sun; Maike Baues; Barbara M Klinkhammer; Josef Ehling; Sonja Djudjaj; Natascha I Drude; Christoph Daniel; Kerstin Amann; Rafael Kramann; Hyojin Kim; Julio Saez-Rodriguez; Ralf Weiskirchen; David C Onthank; Rene M Botnar; Fabian Kiessling; Jürgen Floege; Twan Lammers; Peter Boor

doi:10.1126/scitranslmed.aat4865

Elastin imaging enables noninvasive staging and treatment monitoring of kidney fibrosis

Qinxue Sun, Maike Baues, Barbara M Klinkhammer, Josef Ehling, Sonja Djudjaj, Natascha I Drude, Christoph Daniel, Kerstin Amann, Rafael Kramann, Hyojin Kim, Julio Saez-Rodriguez, Ralf Weiskirchen, David C Onthank, Rene M Botnar, Fabian Kiessling, Jürgen Floege, Twan Lammers, Peter Boor

Biomedical Engineering Department

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Abstract

Fibrosis is the common endpoint and currently the best predictor of progression of chronic kidney diseases (CKDs). Despite several drawbacks, biopsies remain the only available means to specifically assess the extent of renal fibrosis. Here, we show that molecular imaging of the extracellular matrix protein elastin allows for noninvasive staging and longitudinal monitoring of renal fibrosis. Elastin was hardly expressed in healthy mouse, rat, and human kidneys, whereas it was highly up-regulated in cortical, medullar, and perivascular regions in progressive CKD. Compared to a clinically relevant control contrast agent, the elastin-specific magnetic resonance imaging agent ESMA specifically detected elastin expression in multiple mouse models of renal fibrosis and also in fibrotic human kidneys. Elastin imaging allowed for repetitive and reproducible assessment of renal fibrosis, and it enabled longitudinal monitoring of therapeutic interventions, accurately capturing anti-fibrotic therapy effects. Last, in a model of reversible renal injury, elastin imaging detected ensuing fibrosis not identifiable via routine assessment of kidney function. Elastin imaging thus has the potential to become a noninvasive, specific imaging method to assess renal fibrosis.

Original language	English
Article number	eaat4865
Journal	Science Translational Medicine
Volume	11
Issue number	486
DOIs	https://doi.org/10.1126/scitranslmed.aat4865
Publication status	Published - 3 Apr 2019

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10.1126/scitranslmed.aat4865

Elastin imaging enables_SUN_Accepted11March2019_GREEN AAMAccepted author manuscript, 6.74 MB

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Sun, Q., Baues, M., Klinkhammer, B. M., Ehling, J., Djudjaj, S., Drude, N. I., Daniel, C., Amann, K., Kramann, R., Kim, H., Saez-Rodriguez, J., Weiskirchen, R., Onthank, D. C., Botnar, R. M., Kiessling, F., Floege, J., Lammers, T., & Boor, P. (2019). Elastin imaging enables noninvasive staging and treatment monitoring of kidney fibrosis. Science Translational Medicine, 11(486), Article eaat4865. https://doi.org/10.1126/scitranslmed.aat4865

@article{c134a2178e4a4365b929554f7dc3c590,

title = "Elastin imaging enables noninvasive staging and treatment monitoring of kidney fibrosis",

abstract = "Fibrosis is the common endpoint and currently the best predictor of progression of chronic kidney diseases (CKDs). Despite several drawbacks, biopsies remain the only available means to specifically assess the extent of renal fibrosis. Here, we show that molecular imaging of the extracellular matrix protein elastin allows for noninvasive staging and longitudinal monitoring of renal fibrosis. Elastin was hardly expressed in healthy mouse, rat, and human kidneys, whereas it was highly up-regulated in cortical, medullar, and perivascular regions in progressive CKD. Compared to a clinically relevant control contrast agent, the elastin-specific magnetic resonance imaging agent ESMA specifically detected elastin expression in multiple mouse models of renal fibrosis and also in fibrotic human kidneys. Elastin imaging allowed for repetitive and reproducible assessment of renal fibrosis, and it enabled longitudinal monitoring of therapeutic interventions, accurately capturing anti-fibrotic therapy effects. Last, in a model of reversible renal injury, elastin imaging detected ensuing fibrosis not identifiable via routine assessment of kidney function. Elastin imaging thus has the potential to become a noninvasive, specific imaging method to assess renal fibrosis.",

author = "Qinxue Sun and Maike Baues and Klinkhammer, {Barbara M} and Josef Ehling and Sonja Djudjaj and Drude, {Natascha I} and Christoph Daniel and Kerstin Amann and Rafael Kramann and Hyojin Kim and Julio Saez-Rodriguez and Ralf Weiskirchen and Onthank, {David C} and Botnar, {Rene M} and Fabian Kiessling and J{\"u}rgen Floege and Twan Lammers and Peter Boor",

note = "Funding Information: We acknowledge M. Timm and S. Otten for assistance with histopathology; D. M{\"o}ckel for assistance with animal handling; H. K{\"o}nigs, M. Ho{\ss}, and S. R{\"u}tten for transmission electron microscopy; and S. Thor{\"o}e-Boveleth, R. Uerlings, and M. M{\"o}ller for ICP-MS. CRID3 was provided by J. Hall and M. Primiano from Pfizer. This study was financially supported by the German Research Foundation (DFG: SFB/TRR57, SFB/TRR219, BO3755/3-1, and BO3755/6-1), the German Ministry of Education and Research (BMBF: STOP-FSGS-01GM1518A), the European Research Council (ERC: StG-309495 and PoC-813086), the RWTH Interdisciplinary Centre for Clinical Research (IZKF: K7-3, E7-6, and O3-2), the RWTH START program (09/15, 124/14, and 152/12), and the Natural Science Foundation of Ningbo (2017A610190). H.K. is funded by JRC-COMBINE, which is partially funded by Bayer. Additional funding was provided by RWTH START No. 110/15. Publisher Copyright: Copyright {\textcopyright} 2019 The Authors.",

year = "2019",

month = apr,

day = "3",

doi = "10.1126/scitranslmed.aat4865",

language = "English",

volume = "11",

journal = "Science Translational Medicine",

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Sun, Q, Baues, M, Klinkhammer, BM, Ehling, J, Djudjaj, S, Drude, NI, Daniel, C, Amann, K, Kramann, R, Kim, H, Saez-Rodriguez, J, Weiskirchen, R, Onthank, DC, Botnar, RM, Kiessling, F, Floege, J, Lammers, T & Boor, P 2019, 'Elastin imaging enables noninvasive staging and treatment monitoring of kidney fibrosis', Science Translational Medicine, vol. 11, no. 486, eaat4865. https://doi.org/10.1126/scitranslmed.aat4865

TY - JOUR

T1 - Elastin imaging enables noninvasive staging and treatment monitoring of kidney fibrosis

AU - Sun, Qinxue

AU - Baues, Maike

AU - Klinkhammer, Barbara M

AU - Ehling, Josef

AU - Djudjaj, Sonja

AU - Drude, Natascha I

AU - Daniel, Christoph

AU - Amann, Kerstin

AU - Kramann, Rafael

AU - Kim, Hyojin

AU - Saez-Rodriguez, Julio

AU - Weiskirchen, Ralf

AU - Onthank, David C

AU - Botnar, Rene M

AU - Kiessling, Fabian

AU - Floege, Jürgen

AU - Lammers, Twan

AU - Boor, Peter

N1 - Funding Information: We acknowledge M. Timm and S. Otten for assistance with histopathology; D. Möckel for assistance with animal handling; H. Königs, M. Hoß, and S. Rütten for transmission electron microscopy; and S. Thoröe-Boveleth, R. Uerlings, and M. Möller for ICP-MS. CRID3 was provided by J. Hall and M. Primiano from Pfizer. This study was financially supported by the German Research Foundation (DFG: SFB/TRR57, SFB/TRR219, BO3755/3-1, and BO3755/6-1), the German Ministry of Education and Research (BMBF: STOP-FSGS-01GM1518A), the European Research Council (ERC: StG-309495 and PoC-813086), the RWTH Interdisciplinary Centre for Clinical Research (IZKF: K7-3, E7-6, and O3-2), the RWTH START program (09/15, 124/14, and 152/12), and the Natural Science Foundation of Ningbo (2017A610190). H.K. is funded by JRC-COMBINE, which is partially funded by Bayer. Additional funding was provided by RWTH START No. 110/15. Publisher Copyright: Copyright © 2019 The Authors.

PY - 2019/4/3

Y1 - 2019/4/3

N2 - Fibrosis is the common endpoint and currently the best predictor of progression of chronic kidney diseases (CKDs). Despite several drawbacks, biopsies remain the only available means to specifically assess the extent of renal fibrosis. Here, we show that molecular imaging of the extracellular matrix protein elastin allows for noninvasive staging and longitudinal monitoring of renal fibrosis. Elastin was hardly expressed in healthy mouse, rat, and human kidneys, whereas it was highly up-regulated in cortical, medullar, and perivascular regions in progressive CKD. Compared to a clinically relevant control contrast agent, the elastin-specific magnetic resonance imaging agent ESMA specifically detected elastin expression in multiple mouse models of renal fibrosis and also in fibrotic human kidneys. Elastin imaging allowed for repetitive and reproducible assessment of renal fibrosis, and it enabled longitudinal monitoring of therapeutic interventions, accurately capturing anti-fibrotic therapy effects. Last, in a model of reversible renal injury, elastin imaging detected ensuing fibrosis not identifiable via routine assessment of kidney function. Elastin imaging thus has the potential to become a noninvasive, specific imaging method to assess renal fibrosis.

AB - Fibrosis is the common endpoint and currently the best predictor of progression of chronic kidney diseases (CKDs). Despite several drawbacks, biopsies remain the only available means to specifically assess the extent of renal fibrosis. Here, we show that molecular imaging of the extracellular matrix protein elastin allows for noninvasive staging and longitudinal monitoring of renal fibrosis. Elastin was hardly expressed in healthy mouse, rat, and human kidneys, whereas it was highly up-regulated in cortical, medullar, and perivascular regions in progressive CKD. Compared to a clinically relevant control contrast agent, the elastin-specific magnetic resonance imaging agent ESMA specifically detected elastin expression in multiple mouse models of renal fibrosis and also in fibrotic human kidneys. Elastin imaging allowed for repetitive and reproducible assessment of renal fibrosis, and it enabled longitudinal monitoring of therapeutic interventions, accurately capturing anti-fibrotic therapy effects. Last, in a model of reversible renal injury, elastin imaging detected ensuing fibrosis not identifiable via routine assessment of kidney function. Elastin imaging thus has the potential to become a noninvasive, specific imaging method to assess renal fibrosis.

UR - http://www.scopus.com/inward/record.url?scp=85064157734&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.aat4865

DO - 10.1126/scitranslmed.aat4865

M3 - Article

C2 - 30944168

SN - 1946-6234

VL - 11

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 486

M1 - eaat4865

ER -

Elastin imaging enables noninvasive staging and treatment monitoring of kidney fibrosis

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