# Complement-mediated HUS revisited: evolving insights into pathophysiology, diagnosis, and treatment

## TL;DR

This review explores the causes, diagnosis, and treatment of complement-mediated HUS, a rare disease linked to uncontrolled immune system activity.

## Contribution

The paper provides updated insights into the genetic and clinical complexities of CM-HUS and emerging diagnostic and therapeutic tools.

## Key findings

- Genetic variants and autoantibodies contribute to CM-HUS pathogenesis.
- Complement inhibitors like eculizumab improve kidney outcomes and survival.
- Ex-vivo assays and biomarkers may enhance diagnosis and risk assessment.

## Abstract

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.

Created in BioRender. Alyamany, R. (2025) https://BioRender.com/719kful.Flowchart depicting the pathogenesis, genetic derivatives, diagnostic workup, and management of CM-HUS. Pathogenesis shows complement activation leading to microvascular thrombosis. Genetic section highlights variants and autoantibody formation. Diagnosis involves ruling out other TMAs and specific tests. Management includes complement inhibition to improve survival rates in.

Created in BioRender. Alyamany, R. (2025) https://BioRender.com/719kful.