The complement system in kidney diseases.

Abstract

The complement system, a plasma component, was described upon its discovery to augment the opsonization of bacteria by antibodies, ‘complementing’ said antibodies’ antibacterial activity. In its first and foremost role, the complement cascade helps convert pathogen recognition into an effective host defence. Two recent publications in Acta Physiologica have highlighted the role of complement factors in immune cell function, namely monoamine transmitter release from immune cells during immune response and inflammation.1, 2 Since its discovery, however, numerous roles of the complement system in health and disease have been described. Renal physiology and the pathophysiology of renal disease is a common topic in Acta Physiologica: Given the sharp increase in morbidity and mortality from kidney failure in many Western economies during the last century, understanding the mechanisms of normal kidney function,3, 4 renal pathophysiology and the development of kidney failure5-7 and potential regenerative mechanisms8, 9 is highly relevant. Recently, the role of the complement system in renal injury has come into focus, a topic whose underlying mechanisms deserve a closer look. Complement proteins are present in all body fluids, either produced by the liver or locally secreted by numerous cell types.10 Complement activation occurs rapidly and could have devastating effects not only on desired ‘foreign’ targets such as bacterial cells, but also on body cells and tissues. For that reason, cell-bound and soluble complement regulators tightly regulate complement activation mainly in the early steps of those enzyme cascades. An impaired complement regulation caused by mutations or auto-antibodies against complement components leads to complement deposition on tissues. If the balance between complement activation and regulation is disturbed in the kidney, glomerular injuries occur, which are typically found in kidney diseases related to complement dysfunction. Through its close relation to the coagulation system, excessive complement activation induces the formation of thrombi and fibrinolysis.11 So beside its initial description as a ‘complementing factor’ during lysis of bacterial cells, today it is considered to build an important system for remaining tissue homoeostasis.12 Depending on the causing mechanism, complement is activated via different pathways, which all lead to enzyme complex formation on target structures, opsonization and lysis of those structures and release of small anaphylatoxic components to initiate inflammation. The pathways are named alternative pathway (AP), lectin pathway and classical pathway (Figure 1). Although the three pathways differ in the initial activation steps, they result in the formation of complement component 3 (C3) and complement component 5 (C5) converting enzyme complexes, release of C3b-opsonin, anaphylatoxin release and formation of membrane attack complex (MAC). Since the rapid activation of complement, followed by opsonization and cell lysis, body cells tightly regulate complement activation by recruiting soluble or membrane-bound regulators such as Factor H (FH), Factor I (FI), membrane cofactor protein (MCP) and numerous others.13 Nephritis is a traditional term to denote a very heterogeneous disease entity, based on an inflammation of the kidneys which may involve glomeruli, tubuli or the surrounding interstitial tissue. Nephritis pathophysiology is of major interest to pathophysiologists and clinicians alike and involves a multitude of causes.14 Irreversible and progressive glomerular and/or tubulointerstitial fibrosis ultimately lead to reduced glomerular filtration rates (GFR), retention of uraemic toxins and chronic kidney disease (CKD), of which nephritic disease is a frequent underlying condition.15 Dysregulation or overactivation of complement leads to different pathophysiological conditions, among them C3 glomerulopathy, autoantibody-mediated forms of glomerulonephritis, ischaemia reperfusion injury of kidney transplants and atypical haemolytic uraemic syndrome (aHUS). Atypical HUS is characterized by damage of the kidney microvasculature, formation of microthrombi in the renal endothelium, haemolytic anaemia, thrombocytopenia and renal failure leading to end-stage renal disease in about 60% of patients with aHUS.16 More than half of the patients have mutations in one or more of the complement regulators FH, FI, MCP, thrombomodulin and the activators factor B and C3, leading to uncontrolled activation of the alternative pathway. The uncontrolled alternative pathway activation causes endothelial damage and thrombosis. The kidney endothelium is especially dependent on recruiting the soluble alternative pathway regulator FH. Extensive characterization of mutated complement regulators regarding their protective activity leads to a deeper understanding of aHUS pathophysiology and new treatment options. In a mouse model of thrombotic micro-angiopathies, C5 deficiency could ameliorate the effects of alternative pathway activation on renal endothelium.17 Eculizumab, a humanized monoclonal antibody directed against C5, prevents the release of the anaphylatoxin C5a and formation of the MAC. It is administered to patients in the acute phase as well as after renal transplantation to prevent disease recurrence and loss of the renal transplant and is an effective treatment to maintain renal function after aHUS onset.18 C3 glomerulopathy is a spectrum of rare forms of chronic nephritis and is characterized by glomerular damage and changes such as capillary wall thickening proliferation of mesangial and endothelial cells, expansion of mesangial matrix, thickening of peripheral capillary walls and mesangial interposition into the capillary wall.19 It is characterized by C3 cleavage fragment deposition along the glomerular basement membrane. The disease is mainly caused by uncontrolled alternative pathway activation in fluid phase. C3 nephritic factor, an autoantibody against neoepitopes of the C3 convertase complex, is frequently found in patients and clearly associated with C3 glomerulopathy. This antibody increases C3 cleavage by C3 convertase stabilization against the intrinsic decay and the extrinsic decay through complement regulators. In addition, genetic alterations are found in genes of complement components including FH, Factor B, C3 and Factor H-related proteins. Most of these alterations cause reduced complement regulation in fluid phase.12 The glomerular basement membrane is exposed through fenestrated endothelium and requires functional FH for protection from local complement activation.10 There is growing evidence that complement has a significant role in ischaemia reperfusion injury (IRI) of kidney transplants and antibody-mediated graft rejection,20 a topic of high importance for public health institutions. Ischaemia–reperfusion injury of divergent vascular provinces shares common pathophysiological and histological features21 and has extensively been studied in the renal22-25 and cardiovascular26 system. IRI induces a strong inflammatory response in affected tissues and organs, and many pathways and receptors were identified to induce or modulate the hypoxic answer.7, 22, 26 Nevertheless, complement activation plays an important role in IRI. The local production of C3 by renal tubular cells leads to local complement activation, formation of the C5 convertase and therefore a strong release of C3a and C5a. Inflammatory cells are recruited by those anaphylatoxins, whereas tubular cells are damaged by formation of MAC. The pivotal role of the alternative and lectin pathway during IRI was demonstrated in rodent models of renal IRI. Deficiency for the AP component Factor B ameliorated the deleterious effects of renal IRI, whereas mice deficient for mannan-binding lectin (MBL)-A and MBL-C were protected from renal IRI27 However, there is a discrepancy in the role of the complement pathways between rodent models and IRI in human kidneys. Nevertheless, C5a receptor signalling seems to play an important role in the early inflammatory response after renal reperfusion. T cells and antigen-presenting cells produce components of the AP during their interaction. The released anaphylatoxins C3a and especially C5a bind to their receptors on both cell types and increase effector T-cell survival and proliferation. This process supports alloreactive T-cell immunity and therefore kidney graft loss.28 Since a better understanding of complement activation in the pathophysiology of kidney diseases, more than 20 anticomplement activation derived drugs are currently under investigation and give hope for patients suffering from complement-mediated kidney diseases and for the growing numbers of pathological conditions, for example autoimmune and neurological disorders, cancer and sepsis, where complement activation plays an important role.29 None. SR and RM were supported by Bundesministerium für Bildung und Forschung (BMBF) grant FKZ 031A303A.