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

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  • Idris Boudhabhay
  • Victoria Poillerat
  • Anne Grunenwald
  • Carine Torset
  • Juliette Leon
  • Marie V Daugan
  • Francesca Lucibello
  • Khalil El Karoui
  • Amandine Ydee
  • Sophie Chauvet
  • Patrick Girardie
  • Steven Sacks
  • Conrad A Farrar
  • Peter Garred
  • Romain Berthaud
  • Moglie Le Quintrec
  • Marion Rabant
  • Pascale de Lonlay
  • Caroline Rambaud
  • Viviane Gnemmi
  • Veronique Fremeaux-Bacchi
  • Marie Frimat
  • Lubka T Roumenina
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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.

Original languageEnglish
JournalKidney International
Volume99
Issue number3
Pages (from-to)581-597
Number of pages17
ISSN0085-2538
DOIs
Publication statusPublished - Mar 2021

Bibliographical note

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

    Research areas

  • C3 deposition, complement, heme, hemopexin, lectin pathway, rhabdomyolysis-induced acute kidney injury

ID: 61698045