Gene

Complement component 5

Complement system

Biology

Thrombotic microangiopathy

Complement (music)

Complement deficiency

Immunology

Genetics

Complementation

Atypical hemolytic uremic syndrome

Eculizumab

Medicine

Disease

Antibody

Alternative complement pathway

Phenotype

Pathology

Nature Reviews Nephrology

Studies of complement genetics have changed the landscape of thrombotic microangiopathies (TMAs), particularly atypical haemolytic uraemic syndrome (aHUS). Knowledge of complement genetics paved the way for the design of the first specific treatment for aHUS, eculizumab, and is increasingly being used to aid decisions regarding discontinuation of anti-complement treatment in this setting. Complement genetic studies have also been used to investigate the pathogenic mechanisms that underlie other forms of HUS and provided evidence that contributed to the reclassification of pregnancy- and postpartum-associated HUS within the spectrum of complement-mediated aHUS. By contrast, complement genetics has not provided definite evidence of a link between constitutional complement dysregulation and secondary forms of HUS. Therefore, the available data do not support systematic testing of complement genes in patients with typical HUS or secondary HUS. The potential relevance of complement genetics for distinguishing the underlying mechanisms of malignant hypertension-associated TMA should be assessed with caution owing to the overlap between aHUS and other causes of malignant hypertension. In all cases, the interpretation of complement genetics results remains complex, as even complement-mediated aHUS is not a classical monogenic disease. Such interpretation requires the input of trained geneticists and experts who have a comprehensive view of complement biology. Knowledge of complement genetics has improved understanding of the pathogenesis of primary atypical haemolytic uraemic syndrome (aHUS). This Review summarizes current knowledge of complement genetics in aHUS and discusses how complement studies affect the management of patients with other thrombotic microangiopathies.

Thrombotic microangiopathy in aHUS and beyond: clinical clues from complement genetics