REVIEW article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
This article is part of the Research TopicAntibody-Mediated Thrombotic DiseaseView all 7 articles
Complement-Mediated HUS Revisited: Evolving Insights into Pathophysiology, Diagnosis, and Treatment
Provisionally accepted
- Mayo Clinic, Rochester, United States
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Complement-mediated hemolytic uremic syndrome (CM-HUS), commonly referred to as atypical HUS, is a rare thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway, typically triggered by a "two-hit" mechanism. It is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and end-organ damage, most commonly affecting the kidneys. While our understanding of the complement system has advanced significantly, CM-HUS remains a complex, heterogeneous disorder influenced by a spectrum of genetic variants, risk haplotypes, and acquired factors such as anti-factor H autoantibodies. This review highlights the current knowledge of CM-HUS pathogenesis, focusing on genetic variants in regulatory and activating proteins of the complement system. We also discuss the diagnostic complexity posed by incomplete penetrance, overlapping phenotypes, and limitations of genetic and functional assays. Emerging ex-vivo assays and complement biomarkers are explored as tools for refining diagnosis and risk stratification. The use of complement inhibitors such as eculizumab and ravulizumab has significantly improved renal outcomes and survival. This review provides a comprehensive, clinically grounded update on the genetics, pathophysiology, diagnostics, and therapeutic considerations in CM-HUS, aiming to provide clinicians and researchers with a deeper understanding of this complex, complement-driven disease.
Keywords: aHUS, TMA, complement, thrombotic micro angiopathy, Hemolytic uremic syndrome
Received: 30 Apr 2025; Accepted: 08 Dec 2025.
Copyright: © 2025 Alyamany, Moyer, Willrich and Sridharan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Meera Sridharan
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