Inhibition of complement factor C5a or C5aR for cholesterol crystal embolism–related vascular thrombosis with microvascular injury and its consequences
Cholesterol crystal embolism (CCE) implies immunothrombosis, tissue necrosis, and organ failure but no specific treatments are available. As CCE involves complement activation, we speculated that inhibitors of the C5a/C5aR axis would be sufficient to attenuate the consequences of CCE like that with systemic vasculitis. Cholesterol microcrystal injection into the kidney artery of wild-type mice initiated intra-kidney immunothrombosis within a few hours followed by a sudden drop of glomerular filtration rate and ischemic kidney necrosis after 24 hours. Genetic deficiency of either C3 or C5aR prevented immunothrombosis, glomerular filtration rate drop, and ischemic necrosis at 24 hours as did preemptive treatment with inhibitors of either C5a or C5aR. Delayed C5a blockade after crystal injection still resolved crystal clots and prevented all consequences. Thus, selective blockade of C5a or C5aR is sufficient to attenuate the consequences of established CCE and prospective inhibition in high-risk patients may be clinically feasible and safe.
Authors
- Tâmisa Seeko Bandeira Honda
- Axel Vater (ORCID: https://orcid.org/0000-0003-4166-982X)
- Letizia De Chiara (ORCID: https://orcid.org/0000-0002-8548-2031)
- Kai Hoehlig (ORCID: https://orcid.org/0000-0002-4638-4826)
- Chongxu Shi (ORCID: https://orcid.org/0009-0006-2012-2322)
- Lyuben Lyubenov
- Samir V. Parikh (ORCID: https://orcid.org/0000-0001-7023-525X)
- Qiubo Li
- Paola Romagnani (ORCID: https://orcid.org/0000-0002-1774-8088)
- Peter Boor (ORCID: https://orcid.org/0000-0001-9921-4284)
- Patrick Droste (ORCID: https://orcid.org/0000-0001-9809-695X)
- Giulia Carangelo (ORCID: https://orcid.org/0000-0001-6531-1756)
- Elmina Mammadova‐Bach (ORCID: https://orcid.org/0000-0002-5147-0921)
- Kanako Watanabe‐Kusunoki (ORCID: https://orcid.org/0000-0001-8760-8630)
- Chao Han (ORCID: https://orcid.org/0000-0002-0823-9329)
- John P. Shapiro (ORCID: https://orcid.org/0000-0001-6698-2340)
- Hao Long (ORCID: https://orcid.org/0000-0001-5623-9799)
- Donato Santovito (ORCID: https://orcid.org/0000-0003-1811-4746)
- Hans‐Joachim Anders (ORCID: https://orcid.org/0000-0003-2434-2956)
- Chenyu Li (ORCID: https://orcid.org/0000-0002-5402-584X)
- Christian Weber (ORCID: https://orcid.org/0000-0003-4610-8714)
- Yihong Li (ORCID: https://orcid.org/0000-0002-5476-1943)
- Danyang Zhao (ORCID: https://orcid.org/0009-0000-5626-728X)
- Sven Klußmann
Institutions
- Nantong University (CN)
- Hokkaido University (JP)
- The Ohio State University Wexner Medical Center (US)
- Maastricht University (NL)
- Affiliated Hospital of Southwest Medical University (CN)
- Affiliated Hospital of Nantong University (CN)
- Kunming Children's Hospital (CN)
- Munich Cluster for Systems Neurology (DE)
- Meyer Children's Hospital (IT)
- Cyano Biotech (Germany) (DE)
- German Centre for Cardiovascular Research (DE)
- Hokkaido University Hospital (JP)
- University of Florence (IT)
- Ludwig-Maximilians-Universität München (DE)
- RWTH Aachen University (DE)
Publication Details
- Journal
- Kidney International
- Published
- 2024-08-12
- DOI
- https://doi.org/10.1016/j.kint.2024.07.020
- Citations
- 10
- Primary Topic
- Aortic Thrombus and Embolism
- Type
- article
- Field-Weighted Citation Impact
- 4.19
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Ludwig-Maximilians-Universität München
- European Research Council