Relevance of the interactions between the complement and contact coagulation systems on renal pathology

The complement system is a network of soluble and cell surface proteins primarily involved in innate immune responses. Complement signaling is essential for pathogen defence and homeostasis, but an activation-regulation imbalance can lead to tissue damage. This phenomenon has been implicated in kidney diseases such as atypical Haemolytic Uraemic Syndrome (aHUS), frequently associated with dysfunction of the complement regulator Factor H (FH). Physiologically, complement interacts with the coagulation, fibrinolysis, renin-angiotensin and kallikrein-kinin systems (KKS). The KKS is a proinflammatory and procoagulant cascade comprised of the protease prekallikrein, the coagulation factors XI (FXI) and XII (FXII), and the cofactor/substrate high-molecular-weight kininogen. KKS can be activated conformationally or proteolytically. KKS activation in vitro triggers a number of biochemical interactions between FXI, FXII, FH and other complement proteins that result in direct or secondary complement activation. These functional links point to an overall complement pro-activating role for the KKS that has implications for coagulation and immunity, but whose physiological consequences in vivo remain largely unexplored. This review aims to summarize the main physiopathological events of KKS activation in the context of complement-mediated kidney disease, with particular emphasis in aHUS.