The role of the complement system in kidney glomerular capillary thrombosis

Abstract

The complement system is part of the innate immune system. The crucial step in activating the complement system is the generation and regulation of C3 convertase complexes, which are needed to generate opsonins that promote phagocytosis, to generate C3a that regulates inflammation, and to initiate the lytic terminal pathway through the generation and activity of C5 convertases. A growing body of evidence has highlighted the interplay between the complement system, coagulation system, platelets, neutrophils, and endothelial cells. The kidneys are highly susceptible to complement-mediated injury in several genetic, infectious, and autoimmune diseases. Atypical hemolytic uremic syndrome (aHUS) and lupus nephritis (LN) are both characterized by thrombosis in the glomerular capillaries of the kidneys. In aHUS, congenital or acquired defects in complement regulators may trigger platelet aggregation and activation, resulting in the formation of platelet-rich thrombi in the kidneys. Because glomerular vasculopathy is usually noted with immunoglobulin and complement accumulation in LN, complement-mediated activation of tissue factors could partly explain the autoimmune mechanism of thrombosis. Thus, kidney glomerular capillary thrombosis is mediated by complement dysregulation and may also be associated with complement overactivation. Further investigation is required to clarify the interaction between these vascular components and develop specific therapeutic approaches.

Keywords: atypical hemolytic uremic syndrome; coagulation; complement; kidney; lupus nephritis; neutrophil; platelet; thrombosis.

Figure 1

Complement activation pathway. The complement system is activated via three different pathways: classical (CP), lectin (LP), and alternative (AP). The CP is activated by the binding of C1q to antigen-bound antibodies. This reaction activates C1s and C1r, leading to the formation of the CP C3 convertase (C4bC2b). The LP generates the same C3 convertase as the CP, but its activation is caused by mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs). The AP is spontaneously activated via hydrolysis of C3 (C3 (H₂O)), which generates the initial C3 convertase (C3(H₂O)Bb). All three activation routes merge at the cleavage of C3 and lead to the formation of the C5 convertases (C4bC2bC3b and C3bBbC3b), which cleave C5 into C5a and C5b. The C5b fragment forms the membrane attack complex (C5b-9, MAC) by binding to C6, C7, C8, and C9. C9 polymerization is required for C5b-9 generation. C5b-9 creates pores in the membrane and lyses the target cells. The fragment of C3b is opsonin, and C3a and C5a are also known as anaphylatoxins and chemotactic factors, respectively.

Figure 2

Schematic overview of the interaction between the complement system and the coagulation system, platelets, and neutrophils. (i) MASPs can cleave coagulation factors, such as prothrombin, fibrinogen, and factor XIII. (ii) C5a and C5b-9 enhance blood thrombogenicity through upregulation of TF in endothelial cells and neutrophils. (iii) C5a induces UL-VWF secretion and P-selectin expression. Conversely, coagulation factors activate the complement cascade. (iv) Thrombin and plasmin can generate C3a and C5a, whereas plasminogen enhances FI-mediated C3b cleavage in the presence of FH and plasmin degrades C3b. (v) Factor XIa decreases the cofactor and decay acceleration activity of FH and the ability binding of FH to bind to human endothelial cells. Conversely, FH inhibits FXIa activation.