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Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis

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Harvard

Boudhabhay, I, Poillerat, V, Grunenwald, A, Torset, C, Leon, J, Daugan, MV, Lucibello, F, El Karoui, K, Ydee, A, Chauvet, S, Girardie, P, Sacks, S, Farrar, CA, Garred, P, Berthaud, R, Le Quintrec, M, Rabant, M, de Lonlay, P, Rambaud, C, Gnemmi, V, Fremeaux-Bacchi, V, Frimat, M & Roumenina, LT 2021, 'Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis', Kidney International, bind 99, nr. 3, s. 581-597. https://doi.org/10.1016/j.kint.2020.09.033

APA

Boudhabhay, I., Poillerat, V., Grunenwald, A., Torset, C., Leon, J., Daugan, M. V., Lucibello, F., El Karoui, K., Ydee, A., Chauvet, S., Girardie, P., Sacks, S., Farrar, C. A., Garred, P., Berthaud, R., Le Quintrec, M., Rabant, M., de Lonlay, P., Rambaud, C., ... Roumenina, L. T. (2021). Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis. Kidney International, 99(3), 581-597. https://doi.org/10.1016/j.kint.2020.09.033

CBE

Boudhabhay I, Poillerat V, Grunenwald A, Torset C, Leon J, Daugan MV, Lucibello F, El Karoui K, Ydee A, Chauvet S, Girardie P, Sacks S, Farrar CA, Garred P, Berthaud R, Le Quintrec M, Rabant M, de Lonlay P, Rambaud C, Gnemmi V, Fremeaux-Bacchi V, Frimat M, Roumenina LT. 2021. Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis. Kidney International. 99(3):581-597. https://doi.org/10.1016/j.kint.2020.09.033

MLA

Vancouver

Boudhabhay I, Poillerat V, Grunenwald A, Torset C, Leon J, Daugan MV o.a. Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis. Kidney International. 2021 mar;99(3):581-597. https://doi.org/10.1016/j.kint.2020.09.033

Author

Boudhabhay, Idris ; Poillerat, Victoria ; Grunenwald, Anne ; Torset, Carine ; Leon, Juliette ; Daugan, Marie V ; Lucibello, Francesca ; El Karoui, Khalil ; Ydee, Amandine ; Chauvet, Sophie ; Girardie, Patrick ; Sacks, Steven ; Farrar, Conrad A ; Garred, Peter ; Berthaud, Romain ; Le Quintrec, Moglie ; Rabant, Marion ; de Lonlay, Pascale ; Rambaud, Caroline ; Gnemmi, Viviane ; Fremeaux-Bacchi, Veronique ; Frimat, Marie ; Roumenina, Lubka T. / Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis. I: Kidney International. 2021 ; Bind 99, Nr. 3. s. 581-597.

Bibtex

@article{7d15c33cd7194f0a98c00d30efeedc80,
title = "Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis",
abstract = "Rhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury is lacking and the mechanisms of the injury are unclear. To clarify this, we studied intra-kidney complement activation (C3d and C5b-9 deposits) in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. The lectin complement pathway was found to be activated in the kidney; likely via an abnormal pattern of Fut2-dependent cell fucosylation, recognized by the pattern recognition molecule collectin-11 and this proceeded in a C4-independent, bypass manner. Concomitantly, myoglobin-derived heme activated the alternative pathway. Complement deposition and acute kidney injury were attenuated by pre-treatment with the heme scavenger hemopexin. This indicates that complement was activated in a unique double-trigger mechanism, via the alternative and lectin pathways. The direct pathological role of complement was demonstrated by the preservation of kidney function in C3 knockout mice after the induction of rhabdomyolysis. The transcriptomic signature for rhabdomyolysis-induced acute kidney injury included a strong inflammatory and apoptotic component, which were C3/complement-dependent, as they were normalized in C3 knockout mice. The intra-kidney macrophage population expressed a complement-sensitive phenotype, overexpressing CD11b and C5aR1. Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. Hence, heme scavenging and complement inhibition represent promising therapeutic strategies.",
keywords = "C3 deposition, complement, heme, hemopexin, lectin pathway, rhabdomyolysis-induced acute kidney injury",
author = "Idris Boudhabhay and Victoria Poillerat and Anne Grunenwald and Carine Torset and Juliette Leon and Daugan, {Marie V} and Francesca Lucibello and {El Karoui}, Khalil and Amandine Ydee and Sophie Chauvet and Patrick Girardie and Steven Sacks and Farrar, {Conrad A} and Peter Garred and Romain Berthaud and {Le Quintrec}, Moglie and Marion Rabant and {de Lonlay}, Pascale and Caroline Rambaud and Viviane Gnemmi and Veronique Fremeaux-Bacchi and Marie Frimat and Roumenina, {Lubka T}",
note = "Copyright {\textcopyright} 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.",
year = "2021",
month = mar,
doi = "10.1016/j.kint.2020.09.033",
language = "English",
volume = "99",
pages = "581--597",
journal = "Kidney International",
issn = "0085-2538",
publisher = "Nature Publishing Group",
number = "3",

}

RIS

TY - JOUR

T1 - Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis

AU - Boudhabhay, Idris

AU - Poillerat, Victoria

AU - Grunenwald, Anne

AU - Torset, Carine

AU - Leon, Juliette

AU - Daugan, Marie V

AU - Lucibello, Francesca

AU - El Karoui, Khalil

AU - Ydee, Amandine

AU - Chauvet, Sophie

AU - Girardie, Patrick

AU - Sacks, Steven

AU - Farrar, Conrad A

AU - Garred, Peter

AU - Berthaud, Romain

AU - Le Quintrec, Moglie

AU - Rabant, Marion

AU - de Lonlay, Pascale

AU - Rambaud, Caroline

AU - Gnemmi, Viviane

AU - Fremeaux-Bacchi, Veronique

AU - Frimat, Marie

AU - Roumenina, Lubka T

N1 - Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

PY - 2021/3

Y1 - 2021/3

N2 - Rhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury is lacking and the mechanisms of the injury are unclear. To clarify this, we studied intra-kidney complement activation (C3d and C5b-9 deposits) in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. The lectin complement pathway was found to be activated in the kidney; likely via an abnormal pattern of Fut2-dependent cell fucosylation, recognized by the pattern recognition molecule collectin-11 and this proceeded in a C4-independent, bypass manner. Concomitantly, myoglobin-derived heme activated the alternative pathway. Complement deposition and acute kidney injury were attenuated by pre-treatment with the heme scavenger hemopexin. This indicates that complement was activated in a unique double-trigger mechanism, via the alternative and lectin pathways. The direct pathological role of complement was demonstrated by the preservation of kidney function in C3 knockout mice after the induction of rhabdomyolysis. The transcriptomic signature for rhabdomyolysis-induced acute kidney injury included a strong inflammatory and apoptotic component, which were C3/complement-dependent, as they were normalized in C3 knockout mice. The intra-kidney macrophage population expressed a complement-sensitive phenotype, overexpressing CD11b and C5aR1. Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. Hence, heme scavenging and complement inhibition represent promising therapeutic strategies.

AB - Rhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury is lacking and the mechanisms of the injury are unclear. To clarify this, we studied intra-kidney complement activation (C3d and C5b-9 deposits) in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. The lectin complement pathway was found to be activated in the kidney; likely via an abnormal pattern of Fut2-dependent cell fucosylation, recognized by the pattern recognition molecule collectin-11 and this proceeded in a C4-independent, bypass manner. Concomitantly, myoglobin-derived heme activated the alternative pathway. Complement deposition and acute kidney injury were attenuated by pre-treatment with the heme scavenger hemopexin. This indicates that complement was activated in a unique double-trigger mechanism, via the alternative and lectin pathways. The direct pathological role of complement was demonstrated by the preservation of kidney function in C3 knockout mice after the induction of rhabdomyolysis. The transcriptomic signature for rhabdomyolysis-induced acute kidney injury included a strong inflammatory and apoptotic component, which were C3/complement-dependent, as they were normalized in C3 knockout mice. The intra-kidney macrophage population expressed a complement-sensitive phenotype, overexpressing CD11b and C5aR1. Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. Hence, heme scavenging and complement inhibition represent promising therapeutic strategies.

KW - C3 deposition

KW - complement

KW - heme

KW - hemopexin

KW - lectin pathway

KW - rhabdomyolysis-induced acute kidney injury

UR - http://www.scopus.com/inward/record.url?scp=85096740846&partnerID=8YFLogxK

U2 - 10.1016/j.kint.2020.09.033

DO - 10.1016/j.kint.2020.09.033

M3 - Journal article

C2 - 33137339

VL - 99

SP - 581

EP - 597

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 3

ER -

ID: 61698045