Complement activation as a biomarker and a pathogenic factor in rhabdomyolysis-induced acute kidney injury

Abstract

Abstract Rhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury (AKI) being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury (RIAKI) is lacking and the mechanisms of the injury are unclear. We discovered intra-kidney complement activation in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. Moreover, elevation of complement proteins and activation fragments in the urine of RIAKI patients compared to rhabdomyolysis without RIAKI and healthy donors by complement multiplex assays supported a pathogenic role of the complement system. Urinary C5a distinguished AKI, while Ba was elevated even for the patients without AKI, suggesting infra-clinical manifestations. Complement deficient mice (C3−/−, FB−/−) were protected from RIAKI. The transcriptomic signature of RIAKI mice 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. A kinetic mouse model of RIAKI revealed that heme toxicity is the first pathogenic mechanism to injure the tubules, evidenced by kidney transcriptomic signature (QuantiGene RNA assay), followed by neutrophils and inflammatory monocytes, upregulating C5aR1 (flow cytometry). Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. CSL Behring research grant