Complement activation in secondary thrombotic microangiopathies

Abstract Secondary thrombotic microangiopathies (TMA) represent a heterogeneous group of diseases associated with a high risk of kidney failure and death despite available therapeutic strategies. Strong evidence implicates complement dysregulation in the pathogenesis of secondary TMA, and emerging data increasingly suggest that pharmacological blockade of the complement improves the outcomes in patients with secondary TMA. Certain forms of secondary TMA, including postpartum TMA, TMA with coexisting hypertensive emergency and de novo TMA after kidney transplantation exhibit a high prevalence of pathogenic variants in complement genes, similar to those observed in primary atypical hemolytic uremic syndrome. These conditions should be considered as complement-mediated TMA triggered by pregnancy or transplantation, or in which severe hypertension represents a symptom rather than the etiology of TMA. Their optimal management relies on early initiation of complement inhibition. Other etiologies of secondary TMA (i.e. autoimmune diseases, hematopoietic stem cell transplantation, drugs, infections) are typically not linked with complement gene variants and their management primarily focuses on removal of the culprit trigger or treatment of the underlying condition. While well-designed trials are still awaited, a growing body of evidence suggests that complement activation is also involved in the pathopathophysiology of these diseases. Complement inhibitors, which have been associated with better outcomes, should be considered in patients with severe (life- or organ-threatening TMA) or refractory secondary TMA despite adequate management of the underlying condition. This review summarizes the current understanding and future directions in the management of secondary TMA, emphasizing the potential of complement inhibition as therapeutic strategy.