Elsevier

Kidney International

Volume 99, Issue 3, March 2021, Pages 581-597
Kidney International

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

https://doi.org/10.1016/j.kint.2020.09.033Get rights and content

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.

Section snippets

Complement activation in kidneys of RIAKI patients

Ten biopsies of RIAKI patients were collected. The main features of the patients are summarized in Table 1. Kidney biopsies revealed a typical pattern of RIAKI, characterized by acute tubular necrosis (ATN) associated with tubular casts (Figure 1a). C3c staining was negative in the tubules in 8 of the 10 RIAKI patients, and in 2 control subjects: a patient with AKI (creatinine [Cr] = 420 μmol/l) caused by ATN without rhabdomyolysis and an allograft kidney biopsy from a patient 2 days after

Discussion

In addition to myoglobin casts and ATN, which are common histology features for rhabdomyolysis,24 complement deposits occurred in kidneys of mice and patients with RIAKI, independently from the rhabdomyolysis cause. Complement activation occurred intrarenally most likely by the lectin pathway via a C4-bypassing mechanism, and by the alternative pathway via heme. Intrarenal macrophages in RIAKI became particularly sensitive to complement, overexpressing C5aR and CD11b. C3−/− mice were protected

Methods

The complete Methods are provided in the Supplementary Methods.

Disclosure

LTR reports grants from CSL Behring, outside the submitted work. All the other authors declared no competing interests.

Acknowledgments

The cytometric and microscopy analyses were performed at the Centre d’Histologie, d’Imagerie et de Cytométrie (CHIC) and the Centre de Recherche des Cordeliers UMRS1138 (Paris, France). We are grateful to the CHIC team for the excellent technical assistance. CHIC is a member of the Université Pierre et Marie Curie Flow Cytometry Network. We are grateful for excellent technical assistance from the Centre d’Expérimentations Fonctionnelles team of the Centre de Recherche des Cordeliers and for

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    see commentary on page 537

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    These authors contributed equally to this study.

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