Complement-Mediated Kidney Disease

Abstract

From very discovery of the complement cascade, it had an intriguing role in pathophysiology of kidney disease. The hallmark of complement cascade involvement in kidney diseases comprises of immune-complexes deposits in the glomeruli, acting as activation for the classical pathway. However, additional mechanisms of complement activation, namely alternative and lectin pathways are extremely important and prominent in complement-mediated kidney disease. Disease prototype of activation of complement is an atypical hemolytic uremic syndrome with solid activation of complement and C3 glomerulopathy is a hallmark of fluid phase activation of alternative complement pathway. Further research has shown that alternative pathway also plays a role in pathogenesis and progression of other kidney diseases including anti-neutrophil cytoplasmic antibody-associated vasculitis and immune complex-mediated glomerulonephritis as well as IgA nephropathy. A better understanding of complement system’s role in kidney disease has also brought forth novel therapeutic approaches in form of complement cascade inhibitors, revolutionizing the treatment of patients that were faced with unfavorable outcomes. Through this chapter, we bring to you an overview of most prevalent complement-mediated kidney diseases with emphasis on the role of complement in their pathogenesis and the potential for treatment targeting the complement cascade.

1. Introduction

Ever since the complement cascade was first described in the 19th century, researchers have been interested in understanding the role of complement system in pathogenesis of kidney diseases [1]. Plethora of studies has shown that complement deposits paired with decreased levels of complement components in serum play a significant role in complement-mediated kidney diseases, with serum C3 and C4 component levels and C3 and C1q staining of kidney biopsies samples being a mainstay in diagnostic approach and clinical outcome monitoring. As a progression of complement-mediated kidney disease, acute kidney injury (AKI) also stems from complement activation, which acts as an important factor in pathogenesis, affecting all the major structures within the kidney [2].

2. Overview of the complement Cascade system

The complement cascade consists of soluble and cell-bound components, acting in many different roles, from regulatory and executive elements to receptors. White blood cells, platelets, and different tissues interact with the complement system, combining in an inflammatory response aimed to protect against pathogens both infectious and noninfectious [3, 4, 5, 6]. Three distinct pathways play a role in complement cascade activation. The classical pathway is triggered by the formation of immune complexes comprised of immunoglobulin M (IgM) or G (IgG) paired with pathogens or other foreign antigens, which in turn activate C1 complex of the complement system. C1 complex, comprised of three types of subunits, C1q, C1r, and C1s, binds to the Fc portion of either IgG or IgM, inducing the cleaving process that yields C4 and C2 components, which are further cleaved to form a classical pathway C3 convertase, C4bC2a [3, 4, 5, 6]. Lectin pathway is mediated by either mannose-binding lectin (MBL) or ficolin-carbohydrate complex on the pathogen surface. Both MBL and ficolin form complexes with MBL-associated proteins (MASPs), main of which is MASP2. Conformational alterations in MASP2, induced by binding to pathogens, lead to cleavage of C4, with C4b component attaching itself to the surface of the pathogen, bringing about the binding of C2 component and its subsequent cleavage by MASP2, thus producing C2a component and forming a lectin pathway C3 convertase C4bC2a [3, 4, 5, 6]. An alternative pathway is set off by carbohydrates present on foreign surfaces, which causes C3 components to constantly be hydrolyzed in a “tick over” mechanism, forming C3b components. This brings about the recruitment of factor B, which binds to C3b, inducing factor D to cleave factor B and form an alternative pathway C3 convertase C3bBb, which is stabilized with plasma properdin [3, 4, 5, 6].

Both C4bC2a formed through classical and lectin pathways and C3bBb of alternative pathway cleave C3 component, resulting in the release of C3a and C3b, with C3b further amplifying complement activation and phagocytosis. C3b also forms a complex with C3 convertase, forming C5 convertase (C3bBbC3b and C4bC2aC3b), which cleaves C5 component into C5a and C5b, latter of which combines with C6, C7, C8, and multiple C9 components, forming the membrane attack complex (MAC, C5b-9), a terminal complement component responsible for formation of pores by inserting itself into cell membrane, effectively leading to cell lysis, while C3a and C5a components act as anaphylatoxins [3, 4, 5, 6].

Considering the complexity of complement system and its multitude of interactions with various components of immune system, mechanisms of regulation are needed to limit the activity of complement system to proper levels, thus preventing damage to the host cells in both fluid and solid phases [3, 4, 6]. A list of regulatory components and their function is outlined in Table 1. Aside from complement’s role in recognition and eradication of pathogens, it is also included in B and T cell function, acting as mediators and signal modulators in B-cells and playing a role in maintaining T-cell growth, proliferation, and differentiation [4, 5].

Regulator	Function
C1-INH	Inactivation of C1r, C1s, and MASP2
C4 BP	Inhibition of C3 convertase activity
CRIg
CFH	Inhibition of C3 convertase activity
CFI	Serine protease responsible for C3b and C4b cleavage
MCP (CD46)	Cofactor for CFI
DAF (CD55)	Inhibition of C3 convertase activity
CR1 (CD35)	Cofactor for CFI
CR2	Binding of iC3v, C3dg, and C3d formed through CFI cleavage
S protein	Negative regulation of MAC formation and cell lysis
Map44
CD59	Interference with MAC assembly

Table 1.

Overview of complement system regulators.

3. Role of complement Cascade in kidney diseases

As our knowledge of complement system and its intricate interactions with our immune system continues to grow, our understanding of its role in pathogenesis of kidney disease also changed. Long has been known that deposition of immune complexes (IC) in the glomeruli is the cause of classical pathway activation, thus involving the complement system directly in pathogenesis of immune complex-mediated glomerulonephritis [1, 5]. Due to fenestration of glomerular endothelium and negative charge, glomerular basement membrane (GBM) is susceptible to IC and antigen binding, resulting in immune response. Furthermore, antibodies can bind to antigens expressed by the glomerulus itself, either already present there or formed through conformational changes. All this elicits the activation of classical complement pathway [1, 5]. Genetic or acquired dysregulation of alternative pathways is also a major cause of kidney disease, particularly thrombotic microangiopathy, characterized by thrombocytopenia, hemolytic anemia, and acute kidney injury (AKI), is usually present in nonimmune-complex glomerulonephritis [1, 7]. Complement activation plays a major factor in AKI, although it is still to be determined whether complement activation represents a unique occurrence in each type of AKI or is it a general response to injury [2]. Genetic variations of complement regulatory proteins also play a role in pathogenesis of kidney diseases, mainly affecting AP regulators such as factor H and I and membrane cofactor protein (MCP) [5]. Effective application of complement inhibitory drugs, such as complement C5 inhibitor Eculizumab, also supports a key role of complement system in kidney disease, as well as sets up a novel target for potential treatments [5, 8].

3.1 IgA glomerulonephritis

IgA glomerulonephritis (IgAN), also known as IgA nephropathy, is the most common type of glomerulonephritis, with an estimated annual incidence between 0.2 and 5.7 per 100,000, and a leading cause of chronic kidney disease worldwide [1, 6, 9, 10, 11]. IgAN is an autoimmune disease of unanswered etiology with “multihit theory” usually used to describe the pathogenesis of this multifactor disease [6, 9, 10, 11]. Due to poor glycosylation, aberrant IgA1 antibodies (Gd-IgA1) are formed, characterized by presence of galactose-deficient O-glycans. This glycosylation defect appears to be hereditary, although this alone is not enough for the development of disease levels of Gd-IgA1 correlate with the severity and outcome [11, 12]. Gd-IgA1 is targeted by antiglycan autoantibodies, due to exposed terminal N-acetylgalactosamine residues acting as neoepitopes for IgG antiglycan autoantibodies [11, 12]. After the formation of Gd-IgA1-antiglycan IgG immune complexes (Gd-IgA1-IC), they are deposited in the mesangium of kidney, where they initiate inflammatory and proliferative signaling cascades, promoting local inflammation, mesangial matrix production, and mesangial cells proliferation, ending in glomerular and interstitial fibrosis leading to renal injury [10, 11, 12]. Aforementioned Gd-IgA1-IC also causes activation of complement cascade, specifically alternative and lectin pathway, causing the accumulation of C3 components and its subsequent deposition, along with mesangial C4. FHR-gene cluster is also involved in development of IgAN, with elevated plasma FHR1 contributing to inflammation and stronger C3 fragment deposition due to inadequate inhibition through factor H (6,10–13. Furthermore, on one hand, genetic variants of FHR5 contribute to disease susceptibility, due to its role as a complement activator, but on the other hand, FHR1 and FHR3 deficiency have demonstrated a protective role [6]. As for the lectin pathway, mannose-binding lectin and L-ficolin, both acting as pattern recognition molecules in charge of activating lectin pathway, have been detected in the glomeruli of IgAN patients, with genetic variants in genes for mannose-binding lectine-2 (MBL-2) representing a risk factor in progression of IgAN [6, 10, 11, 12, 13]. In addition to primary IgAN, there is also so-called “secondary IgAN,” usually associated with other systemic conditions and sharing pathophysiological processes, histological and clinical manifestation with primary IgAN [11].

Considering a complex and multiple interactions needed for development of disease, clinical manifestations of IgAN can come in a plethora of clinical syndromes [11]. The most common clinical manifestation of IgAN in adults includes a combination of asymptomatic hematuria with fluctuating levels of proteinuria with or without chronic kidney disease [10, 11, 12]. Hematuria in IgAN can be either macroscopic gross hematuria (MGH) or microscopic hematuria, with MGH being more common in pediatric population and early stages of adult IgAN [12]. MGH is usually accompanied by mucosal infections (either respiratory or gastrointestinal), pointing at dysregulation of mucosal immune system and mucosa-kidney axis as potential contributing factors to pathogenesis of hematuria [12]. Proteinuria paired with hypertension and reduction in glomerular filtration is key factor in chronic kidney disease, with amount of proteinuria being especially relevant, considering that more than 0.5 g/day of protein is associated with poor renal outcome. On rare occasions, nephrotic syndrome can occur and should not be confused with more common “nephrotic-range” proteinuria, which usually is not paired with hypoalbuminemia. Although renal function impairment in IgAN usually progresses chronically, acute kidney injury (AKI) can develop in two specific cases: First being in rapidly progressive glomerulonephritis and second due to acute tubular injury from red blood cells or heme toxicity. Aside from all of the above, systemic forms of IgAN can also occur, more frequently in pediatric population. These include Henoch-Schönlein purpura and IgA vasculitis. Also, pathology finding of thrombotic microangiopathy (TMA) is present, in spite of insufficient laboratory evidence. Clinical outcomes are also varied, ranging from spontaneous remission in 5–15% to rapidly progressive glomerulonephritis and end-stage renal disease [10, 12, 11]. Considering that light microscopy findings can be varied, diagnosis of IgAN relies heavily on immunofluorescent microscopy, which is used not only to visualize IgA deposits in the mesangium but also to show C3 deposits, pointing toward complement activation in glomeruli [10, 11].

For now, there is no curative treatment available for IgAN. Treatment is usually focused on comprehensive supportive care, including angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers for regulation of hypertension, statins, low sodium diet, and avoiding nephrotoxic drugs. Control of proteinuria is essential for renal function improvement. If renal function continues to deteriorate, a 6-month course of corticosteroids can be recommended [10, 11]. With new knowledge coming to light regarding the role of complement in IgAN, complement inhibition presents a novel treatment modality for IgAN [11, 12, 14]. Eculizumab, anti C5 complement monoclonal antibody, was used off-label for IgAN in 2 patients [15, 16], with results being lackluster, with only temporary clinical improvement, due to the fact that IgAN is characterized by primarily C3 deposits, while eculizumab blocks C5 component of complement, thus not preventing accumulation of C3 [1]. This implies that other complement inhibitors, targeting higher instances of complement cascade, such as factor B inhibitor LNP023, MASP-2 inhibitor OMS721, and anti-C3 compstatin and APL-2, could potentially be more useful in preventing the role of complement in IgAN [11, 12, 17].

3.2 Membranous nephropathy

Membranous nephropathy (MN), also known as membranous glomerulonephritis, is an autoimmune disease caused by an accumulation of immune complexes in the subepithelial space of the glomerular capillary wall, and thus it is the most common cause of nephrotic syndrome in adults. Rarely affecting children, usual age of onset is between 50 and 60 years of age [1, 6, 10, 18, 19]. Main cause of MN is accumulation of circulating autoantibodies that target specific antigens on the surface of podocytes. Being of IgG type, these antibodies form immune complexes that accumulate in the subepithelial space, thus distorting physiological function of basement membrane [10, 18]. Commonly targeted surface antigen is the podocyte protein called M-type phospholipase A2 receptor (PLA2R), which is affected in 70 to 80% of cases, while in around 3 to 5% of cases anti-thrombospondin type-1 domain-containing protein 7A (THSD7A) is the main antigen [10, 20]. MN is classified as either primary, caused by autoantibodies targeting aforementioned proteins, or secondary, caused by other autoimmune diseases, malignant tumors, infection, or drugs [10, 18, 19]. The role of complement system is not fully elucidated in pathophysiology of MN. Complement components, especially C3 and C5b-9, can be found alongside immune-complex deposits in primary MN. Although both anti-PLA2R and anti-THSD7A antibodies are mostly of IgG4 subtype, which are unable to interact with C1q complement component making it subsequently unable to activate the classical pathway of complement activation, there is still evidence of classical pathway activation, along with lectin pathway and alternative pathway activation. Classical pathway can be activated through other subtypes of antibodies, namely IgG1,2, and 3, which could explain the presence of C1q components in renal biopsies. On the other hand, lectin pathway activates in patients exhibiting mannose-binding lectin (MBL) in the glomeruli. Due to “tick-over” phenomenon, alternative pathway is constitutively active. Taking into account all of the aforementioned complement pathways, it is highly likely that different levels of activity are present in different patients [6, 10, 18, 21]. Pathohistological approach to diagnosing MN includes light microscopy, which shows thickened glomerular capillary wall, due to deposition of immune complexes and complement components, with visible spikes, immunofluorescent microscopy, which displays IgG staining abetted by C3 complement components, and anti-PLA2R antibodies. Furthermore, subclass staining for IgG may help in classification. Electron microscopy can be used, where available, to show subepithelial deposits. Findings of IgG4 antibodies and deposits located only in subepithelial space point toward primary MN, while additional findings of deposits on intramembranous and mesangial levels with IgG1, 2, and 3 subclasses of antibodies imply a secondary MN [10]. MN usually presents as nephrotic syndrome, although non-nephrotic proteinuria is present in 20% of patients [10]. Treatment of MN is largely only supportive and aimed at managing hypertension, reducing edema, and reducing protein excretion. To that effect, ACEI or ARB is prescribed, preferable over other antihypertensive drugs due to their renoprotective properties. Patients with hyperlipidemia and coagulation dysregulation should be introduced to statins and anticoagulants, respectively. If the patients are unresponsive to conservative treatment, alkylating agents (such as cyclophosphamide or chlorambucil) paired with corticosteroids can be attempted. Besides that, calcineurin inhibitors as monotherapy and mycophenolate mofetil can be used. Considering that complement system plays a role in pathogenesis of MN, targeting specific key steps in complement cascade is an enticing therapeutic target. Ongoing studies regarding APL-2, which binds C3 and C3b, act as their inhibitor, while eculizumab, a C5 complement component blocker, has already seen use in MN, although to poor effect regarding proteinuria [19, 10].

3.3 C3 Glomerulopathy

C3 glomerulopathy (C3G) is a clinical and pathological condition primarily caused by dysregulation of the alternative pathway of complement system, specifically the fluid phase [6, 10, 22]. C3G is relatively rare, with incidence ranging from 1 to 3 cases per million per year, and affects children and adolescents more often [22]. There are two main subtypes of C3G, one of them being dense deposit disease (DDD) characterized by electron-dense deposits within GBM and other being C3 glomerulonephritis (C3GN), in which deposits are found along subendothelial side of GBM but also in the mesangium, differentiating two subtypes [1, 6, 10, 22]. Classical definition of C3G lies upon positive immunofluorescence staining for C3, which should be either isolated or at minimum two orders of magnitude greater than other immune reactants. But this criterion is not infallible, as immunofluorescence results can be borderline and inconclusive. Furthermore, complement abnormalities can also be found in membranoproliferative glomerulonephritis (MPGN) and lastly, immunofluorescence stain used in clinical settings marks primarily C3c, but in C3G, the predominant accumulated compound is C3dg. Taking all of this into an account, a novel pathogenic classification was proposed, identifying four different clusters with main differences being in levels of C3 and prevalence of complement genetic abnormalities [22, 23].

The focal point of pathogenesis of C3G is a dysregulation of alternative complement pathway brought forth by genetic abnormalities, autoantibodies against complement components, or nephritic factors (NeFs) responsible for C3 and C5 convertase stabilization [6, 10, 22]. Genetic abnormalities are present in around 25% of patients, with C3 gene, complement factor B, H, and I genes (CHB, CFH, and CHI) and complement factor H-related protein gene (CFHR) being the most affected. Pathogenic variants in C3 disrupt cleavage of the molecule due to erroneous recognition sites for CFH and CHI binding, while on the other hand, CFB pathological variants bestow gain-of-function properties. Variants in CFI genes diminish its cofactor activity and CFH variants have a profound effect on N-terminal regions, causing disruption in fluid phase regulation [6, 10, 22]. NeFs are a heterogenous group of antibodies that target neoepitopes in C3 or C5 convertase. This results in stabilization of both convertases, leading to a prolonged half-life. Two main types of NeFs have been described: C5NeFs, properdin-dependent NeFs-targeting epitopes of C5 convertase, mainly found in C3GN, and C3NeFs, properdin-independent NeFs targeting C3 epitopes in DDD [6, 10, 22]. In addition to these main antibodies, C4neFs, targeting classic and lectin pathway C3 convertase, was also described, along with autoantibodies against CFH, CFB, and C3b but their role remains uncertain [22].

Although C3G usually presents in a wide array of clinical manifestations, ranging from incidental asymptomatic microscopic hematuria to chronic kidney disease, most frequent manifestation is proteinuria with preserved kidney function [1, 6, 10, 22, 24]. Considering an infection can precede C3G, differential diagnosis must include postinfectious glomerulonephritis, with specific markers like anti-streptolysin O and deoxyribonuclease B antibodies. There is a number of possible external, non-renal manifestations, such as retinal drusen and atrophy and acquired partial lipodystrophy. In majority of cases, C3G is progressive, with almost half the patients progress to end-stage kidney disease in 5-year period [1, 6, 10, 22, 24].

Diagnosis of C3G depends on histopathologic findings of kidney biopsies. Under light microscopy the most prevailing finding is that of membranoproliferative glomerulonephritis, found in more than 50% of cases, but findings of mesangial proliferative, diffuse endocapillary proliferative and diffuse sclerosing glomerulonephritis can also be present. Crescents, either cellular or fibrocellular can also be found. Immunofluorescence staining is used to highlight C3 in the mesangium and capillary walls, with no considerable staining for immunoglobulins, C1q, and light chains. Electron microscopy is used to distinguish between C3GN and DDD. In addition to histopathologic procedures, genetic and molecular analysis pertaining to complement systems can be helpful to acquire valuable information regarding pathophysiological mechanisms [22, 24].

There is no single ideal treatment for C3G, as treatment modalities are etiologically dependent. Renin-angiotensin system (RAAS) inhibitors are used as a supportive therapy, targeting hypertension and proteinuria. Furthermore, recent studies have shown that renin possesses an intrinsic ability to cleave C3, thus acting as an accelerator of alternative pathway activation, which further justifies the use of RAAS inhibitors [10, 22]. Immunosuppression, usually consisting of either mycophenolate mofetil or rituximab, has also been proven to produce better outcomes, especially if paired with corticosteroids [22, 24]. The use of complement inhibitors is justified, considering involvement of complement activity in pathophysiological mechanism of C3G, but evidence remains limited, with varying results [6, 10, 22, 24].

3.4 Postinfectious glomerulonephritis

Postinfectious glomerulonephritis (PIGN) is a type of glomerulonephritis that develops after infections, most common of which include streptococcal pharyngitis, other upper respiratory tract infections, gastroenteritis, skin infections, and pneumonia, although there have been reports of no recent infections preceding PIGN [1, 10, 25]. PIGN shares its clinical and pathological traits with C3G, with both entities being preceded by infections and sharing dysregulations in alternative complement pathways, suggested by low C3 and normal C4 plasma levels. PIGN is usually a rare occurrence as a result of adequate and effective treatment of preceding infection, but when it does occur, it is self-limiting. However, “atypical postinfectious glomerulonephritis” is a phrase used to describe a type of PIGN characterized by alternative pathway activation that causes it to persist, with possibility of progressing, with persistent proteinuria and hypocomplementemia, into end-stage kidney disease due to decline in renal function [1, 10, 25]. This complement involvement is in support of findings pointing toward similarities between PIGN and C3G that could potentially cause a diagnostic challenge [1, 10, 25, 26].

Clinical presentation of PIGN is varied, typically consisting of hematuria, nephrotic or less than nephrotic range proteinuria, azotemia, hypertension, peripheral edema, and anemia [1, 10, 25].

Pathological findings pointing toward diagnosis of PIGN consist of proliferative glomerulonephritis with subepithelial “humps” visible on electron microscopy, paired with bright C3 staining with or without IgG deposits on immunofluorescence microscopy [1, 10, 25].

Due to PIGN being a primarily self-limiting disease, supportive therapy is modality of choice, consisting mainly of fluid and electrolyte control paired with antihypertensives, correction of potential acidosis and, if required, dialysis [1, 10, 25].

3.5 Atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is a disease primarily caused by dysregulation in an alternative pathway of complement. Majority of aHUS patients are adults, but around 5 to 10% are pediatric patients, making it a relatively rare but complicated disease to battle [27, 28, 29]. Although mutations of complement regulatory proteins are present in majority of cases, in some instances, they are not phenotypically active, thus requiring a trigger, usually in form of bacterial or viral infections, parasites, other autoimmune diseases, and drugs, including chemotherapy and vaccines. Due to active COVID-19 pandemic, special mention needs to be put on SARS-CoV-2 as a potential novel trigger of aHUS [27, 29].

The main pathophysiological mechanism of aHUS is the loss-of-inhibition of regulatory proteins of the alternative pathway of complement system, namely CFH, CFI, and membrane-cofactor protein (MCP). This occurs either through genetic mutations targeting specific genes coding for said regulatory proteins or through activity of anti-CFH antibodies. These changes, paired with a trigger that induces complement activation through an alternative pathway, cause the loss of protection of endothelial cells, making them susceptible to complement-induced damage. Loss-of-inhibition of regulatory proteins is not the only possible mechanism. Gain-of-function mutations in genes coding for C3 complement component and CFB, main components of alternative pathway C3 convertase are also connected to overactivation of alternative complement pathway, thus resulting in pro-inflammatory and procoagulant activity of endothelial cells. This pathophysiological mechanism results in development of thrombotic microangiopathy (TMA), a characteristic pathology finding in aHUS and source of its clinical presentation [1, 27, 28, 29].

Clinical presentation mainly consists of hemolytic anemia, thrombocytopenia, and end-organ damage, most commonly in form of renal failure, which is characterized by oliguria and hypertension [27, 28, 29]. Other symptoms can also occur, most often cardiovascular and neurological but also pulmonary, gastrointestinal, and dermatological, making aHUS a complicated clinical entity to recognize [27, 28, 29].

Diagnostic approach to aHUS is one of exclusion, considering there are no direct tests for it and available biomarkers are not completely dependable. There must be no associated disease present, no criteria met for Shiga toxin-producing E. coli HUS (STEC HUS), which is the most common cause of aHUS, and no criteria met for thrombotic thrombocytopenic purpura (TTP), namely serum ADAMTS 13 activity should be under 10%. Complement system activity investigation is strongly advised including measuring of C3, C4, CFH, and CFI plasma concentrations, measuring of MCP expression, anti-CFH antibody levels, and sC5b-9 levels [27, 28, 29].

Eculizumab and ravulizumab, monoclonal antibodies that act as complement component C5 blockers, are treatment of choice in aHUS. Other than that, plasma exchange therapy and plasma infusions can be used if complement blockers are unavailable or until an aHUS diagnosis can be confirmed with exclusion. Complement C5 blockers prevent cleavage of C5 into C5a and C5b, which has a twofold effect, negating pro-inflammatory activity of C5a and also disrupting the formation of C5b-9 (MAC) complexes, altogether resulting in end of acute hemolysis and stabilization in both platelet count and renal function [10, 27, 28, 29].

3.6 ANCA-glomerulonephritis

Vasculitis is an inflammation of the blood vessels, specifically their wall, which brings about structural and functional damage. Vasculitis is classified using the 2012 International Chapel Hill Consensus Conference (CHCC), which defines vasculitis according to vessel size [1, 30, 31]. Antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis (AAV) is subdivided into three clinical entities: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). AAV is relatively uncommon, with incidence ranging up to twenty per million population per year. It is also worth noting that incidence increases with age, reaching its peak around 60 to 70 years of age [1, 30, 31]. Familial hereditary forms of AAV have been described but are rare [30]. The main role in AAV is given to ANCA autoantibodies, which target cytoplasmic antigens of primary neutrophil granules and monocytic lysosomes. Most commonly targeted antigens are proteinase 3 (PR3) and myeloperoxidase (MPO). PR3-ANCA is commonly related to GPA while MPO-ANCA is found in MPA or renal-limited vasculitis [1, 30, 31]. Other than that, there exists ANCA-negative patients, which exhibit clinical features and pathology usually found in AAV. These patients usually have a renal-limited disease, with fewer systemic features [30].

Neutrophils are the main arbiters of vessel injury found in AAV, stimulated by inflammatory cytokines (namely tumor necrosis factor α and interleukin 1), lipopolysaccharide, or complement component C5a, due to either infection or other types of inflammation. This causes a shift of MPO and PR3 to neutrophil surface, priming the neutrophils, making it easy for ANCAs to bind to these antigens, evocating a potent cellular activation [1, 30, 31]. All of this results in degranulation of neutrophils and release of reactive oxygen species, causing vessel damage. Due to extrusion of neutrophil extracellular traps (NETs), neutrophil undergo NETosis, a special form of cell death. These NETs have a multitude of functions, including directly injuring endothelium, transferring MPO or PR3 to endothelium and dendritic cells for antigen presentation, and activating the alternative pathway of complement [1, 30, 31]. Tissue deposition of PR3 and MPO, paired with chemokines, brings about the recruitment of autoreactive T cells and monocytes, further propagating tissue injury [1, 30, 31]. Originally thought that complement involvement was limited due to scarce complement depositions in kidney biopsies and lack of hypocomplementemia, novel studies demonstrate a role of alternative pathway of complement in pathogenesis of AAV, with C5a and C5a receptor (CD88) being the center of this process [30, 31, 32]. Activated neutrophils release properdin, an alternative pathway promotor, which activity propagates generation of C5a through an alternative pathway, which in turn binds to C5a receptor, further priming and activating neutrophils, thus creating an amplification loop [30, 31, 32, 33].

ANCA-GN is characterized by necrotizing and/or crescentic GN without significant immune-complex depositions, either on immunofluorescent or electron microscopy. In some cases, small amounts of IgG and C3 deposits can be found, which is associated with more severe disease [30].

Clinical presentation of GPA consists of constitutional symptoms, chronic respiratory illness, arthralgia and leukocytoclastic skin rash, lung nodules and, most importantly, acute kidney injury (AKI), which has been proven by pathological findings, including necrotizing and crescentic pauci-immune GN and PR3-ANCA positive results. On the other hand, MPA is distinguished from GPA by absence of granulomatous manifestations and positive MPO-ANCA finding [1, 30, 31]. AKI is very common in AAV and the most important factor in predicting mortality, with patients who present with glomerular filtration rate lesser than 50 mL/min having a 50% risk of death of kidney failure in 5-year time. Typical presentation includes rapidly progressive GN paired with sub-nephrotic range proteinuria, microscopic hematuria, and hypertension. To minimize the progression of kidney presentation, timely initiation of therapy is crucial [1, 30, 31]. Aside from kidney involvement and constitutional symptoms (fatigue, myalgia, and fever), systemic features include lung involvement, namely pulmonary necrotizing granulomatous lesions, upper respiratory tract disease, including rhinitis, sinusitis, otitis media, and granulomatous inflammation, purpuric rash on extremities (secondary to leukocytoclastic vasculitis), cutaneous nodular lesions, peripheral neuropathy, mesenteric vasculitis (with abdominal pain and blood in stool), and cardiac involvement can be present. In rare instances, vasculitis of the liver and pancreas can mimic hepatitis or pancreatitis, making differential diagnosis difficult [1, 30, 31].

Approach to treatment includes several phases, the first being induction phase, which lasts for three to six months and is used to stop the inflammation process and lessen tissue damage. Next is the maintenance phase, which lasts from 24 to 48 months with the aim of preventing relapse. Glucocorticoids combined with either cyclophosphamide or rituximab represent a standard of care for induction phase, while in refractory disease, it is recommended to switch the initial induction agent. Aside from cyclophosphamide and rituximab, mycophenolate mofetil can also be used, but with a greater risk of relapse. Plasma exchange can also be used due to its ability to remove ANCAs and other inflammatory mediators. With newly identified role of alternative complement pathway, complement inhibition is a novel approach to treatment. Avacopan, oral C5a receptor (CD88) inhibitor, and IFX-1, a monoclonal antibody targeting C5a, are in clinical trials, with avacopan already being a feasible therapeutic option instead of corticosteroids [1, 30, 31, 32].

4. Conclusion

Over the years, a large body of evidence has been accumulated pointing toward complement system as a major pathogenesis factor in many kidney diseases considering that kidneys are uniquely susceptible to complement-mediated inflammation. It is clear that involvement of complement in kidney disease represents a fruitful field of research, hoping to better understand pathogenesis of many kidney diseases and also provides a novel target for potential treatment.