nature reviews nephrology https://doi.org/10.

1038/s41581-023-00766-1

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The role of complement

in kidney disease
Vojtech Petr 1,2
& Joshua M. Thurman 2

Abstract Sections

The complement cascade comprises soluble and cell surface proteins Introduction

and is an important arm of the innate immune system. Once activated, The complement system
the complement system rapidly generates large quantities of protein Complement-mediated kidney
fragments that are potent mediators of inflammatory, vasoactive and disease
metabolic responses. Although complement is crucial to host defence Complement as a downstream
and homeostasis, its inappropriate or uncontrolled activation can also mechanism of kidney injury

drive tissue injury. For example, the complement system has been known Susceptibility of the kidney to
complement-mediated injury
for more than 50 years to be activated by glomerular immune complexes
and to contribute to autoimmune kidney disease. Notably, the latest Therapeutic options for
targeting the complement
research shows that complement is also activated in kidney diseases cascade
that are not traditionally thought of as immune-mediated, including
Complement biomarkers
haemolytic–uraemic syndrome, diabetic kidney disease and focal
Conclusions
segmental glomerulosclerosis. Several complement-targeted drugs
have been approved for the treatment of kidney disease, and additional
anti-complement agents are being investigated in clinical trials. These
drugs are categorically different from other immunosuppressive agents
and target pathological processes that are not effectively inhibited
by other classes o­f i­mm­un­os­up­pr­es­sants. The development of these
new drugs might therefore have considerable benefits in the treatment
of kidney disease.

1
Institute for Clinical and Experimental Medicine, Prague, Czech Republic. 2University of Colorado Anschutz
Medical Campus, Aurora, Colorado, USA. e-mail: joshua.thurman@cuanschutz.edu

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Key points complement include rapid destruction of bacteria, silent removal of

apoptotic cells, and neuron pruning, to name but a few5,6. Furthermore,
the complement cascade cross-talks with other systems and path-
•• The complement system is activated in kidney diseases of different ways, including the adaptive immune response, the inflammasome,
aetiologies, including diseases involving immune complex formation, Toll-like receptors and the coagulation system7–9. The general structure
thrombotic microangiopathy, C3 glomerulopathy, glomerulosclerosis of the complement cascade is similar in humans and rodents, enabling
and acute kidney injury. investigators to study complement biology in preclinical models10.
However, interspecies differences exist11,12, and caution is required
•• Experimental and clinical evidence suggests that the complement when extrapolating findings from animal models to human disease.
cascade contributes to injury in diseases that are not traditionally
regarded as immune mediated, including diabetic kidney disease Complement activation
and focal segmental glomerulosclerosis. The complement system comprises multiple soluble proteins. These pro-
teins are predominantly synthesized in the liver but are also expressed
•• The mechanisms of complement activation, including the activation by other cell types, including tubular epithelial cells13,14. Several com-
pathways involved, vary among different kidney diseases, as do their ponents of the complement cascade have protease activity and the
downstream pathological effects. sequential cleavage of proteins in the cascade allows the rapid and
well-orchestrated generation of effector molecules at the site of acti-
•• Deposition of immune complexes in the glomerular capillaries, vation. Complement activation can occur through three different path-
the high local concentration of complement proteins and the ways: the classical, lectin, or alternative pathways. Activation through
delicate system of complement regulation within the kidney might all each pathway generates C3-convertases, which are enzymes that cleave
contribute to its unique susceptibility to complement-mediated injury. circulating C3 into C3a and C3b fragments.
Activation of the classical pathway is initiated by IgG or IgM bound
•• Many complement-inhibiting drugs have been approved, and to target antigens, and this pathway is activated in glomerulonephritis
additional agents targeting different components along the associated with the formation of immune complexes15 (Fig. 1). Although
complement cascade are being investigated in clinical trials. the classical pathway was the first to be described, phylogenetically, the
lectin pathway is probably the oldest16,17. The lectin pathway is activated
•• Complement-inhibiting drugs target immune system pathways that by pattern recognition proteins, such as mannose-binding lectin (MBL),
are not directly blocked by other immunosuppressive agents. that bind to specific molecular targets, predominantly sugars. These
ligands are displayed on the outer surface of bacteria and on damaged
host cells18. The lectin pathway is involved in the pathogenesis of several
Introduction kidney diseases19,20, possibly because lectin pathway activators can bind
Although the complement system was first described more than to specific glycans displayed on injured kidney cells (Fig. 1).
100 years ago1, the biology of this protein cascade is still an area of C3b generated by either the classical or the lectin pathway can
active investigation. Research has revealed that the complement system be used to form the alternative pathway C3 convertase (C3bBb); the
is activated in kidney diseases of widely different aetiologies, including alternative pathway therefore amplifies the activity of the other two
various forms of glomerulonephritis, tubulointerstitial disease, throm- complement activation pathways21,22. C3b generated by the alterna-
botic microangiopathy (TMA) and transplant rejection2–4. However, the tive pathway can itself be incorporated to form additional C3bBb
molecular triggers for complement activation and the downstream convertases, thereby creating a positive feedback loop. In addition, the
mechanisms of injury differ between these diseases. The role of com- alternative pathway is characterized by continuous low-level activa-
plement in the pathogenesis of kidney disease is therefore not a single tion of plasma C3 to form C3b in a process called ‘tickover’23. Notably,
linear process, but is rather dependent on disease and context. Many C3 is also cleaved by proteases that are not ordinarily categorized as
complement-inhibiting drugs are in clinical development, including complement components, such as neutrophil elastase and thrombin9,24.
molecules that target different components within the cascade. The C3b generated by any of these proteases feeds into the alternative
availability of these agents raises the possibility that anti-complement pathway amplification loop, which is therefore a potent arm of the
therapies might eventually be matched to specific kidney diseases complement system.
based on the drug’s mechanism of action. The other half of the alternative pathway convertase, the Bb
In this Review, we examine the different mechanisms that cause fragment, is generated when the protease Factor D cleaves factor B
complement activation across the spectrum of kidney diseases. We into Ba and Bb fragments. Factor D is an ~24 kD plasma protein that
also discuss the unique anatomical and biochemical conditions in the is filtered by the kidney. Consequently, levels of factor D increase in
kidney that make it susceptible to complement-mediated injury in plasma of patients with reduced kidney filtration25. High plasma con-
diverse pathological settings. Finally, we consider how complement centrations of factor D, in turn, increase alternative pathway activity26,
inhibitory drugs can best be integrated with other effective treatments as evidenced by the high levels of Ba in patients with chronic kidney
for these diseases. disease (CKD)27. Theoretically, CKD might therefore exacerbate any
alternative pathway-mediated disease owing to increased levels of
The complement system factor D in plasma.
The complement system is a network of soluble and membrane-bound An interesting aspect of complement activation is that the
proteins. Complement is usually regarded as part of the innate immune fragments of two circulating complement proteins, C3 and C4, can
system and mediates many of the downstream effects of immuno- attach to nearby biological surfaces through covalent opsonization28.
globulins and other pattern recognition molecules. The functions of C4b is a constituent of the C3 convertase (C4bC2a) of the classical and

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a Healthy b Immune complex

Classical Alternative Lectin Glomerulus C2, C4 Classical Alternative Terminal

pathway pathway pathway pathway pathway pathway

C4Bp FH,FI
C3 C5
C1q
Podocyte Endothelial IgG or IgM C5a
cell Antigen
C5b–9
FH CD59 GBM C5
C4d C4bC2a C3b convertase
CD46
CD55 GPI anchor

Slit diaphragm
d AAV
c DKD and FSGS
C2, C4 Lectin Alternative Terminal Neutrophil PR3 and/or MPO
pathway pathway pathway

C3 C5
Loss of c5aR
MBL regulators C3b C5a C5a
Saccharide (+) Vascular
C5 damage ANCA
↑ Alternative
C4bC2a convertase
pathway activity
O2

O2

e
C3 C3G aHUS C3
Alternative C3bBb Alternative C3b Regulators
pathway pathway
C3bBb
C3a C5

Regulators C3b C5a

C5
C3b convertase
C3b
C3b iC3b

Fig. 1 | Mechanisms of complement activation in glomerular disease. enhanced activation within the glomerulus. d, Anti-neutrophil cytoplasmic
Activation of the classical, lectin and alternative pathways leads to the deposition antibody (ANCA)-associated vasculitis (AAV). Various stimuli might prime
of C3b on glomerular capillaries. a, In healthy kidneys, C3b is efficiently neutrophils to expose proteinase 3 (PR3) or myeloperoxidase (MPO), which are
inactivated by soluble and membrane-bound complement regulators. recognized by ANCA. Binding of ANCA leads to neutrophil activation, including
b, Immune complex-mediated diseases. IgG or IgM bind to deposited or in situ induction of an oxidative burst and degranulation. Furthermore, activated
antigens and generate the classical pathway C3 convertase (C4bC2a). Deposited neutrophils might release factors that activate the alternative pathway. C5a induces
C4b is converted to C4d, which can serve as a biomarker of classical pathway upregulation of PR3 and MPO on neutrophils, propagating this process. e, C3
activation. The C3 convertase cleaves C3, and this process is amplified through glomerulopathy (C3G) and atypical haemolytic–uraemic syndrome (aHUS). In
the alternative pathway. Activation also generates C5 convertases (C4b2a3b C3G, impaired regulation of the alternative pathway leads to overactivity in the
and C3bBbC3b), which cleave C5 and activate the terminal pathway. c, Diabetic fluid phase, and soluble fragments might contribute to kidney injury84. However,
kidney disease (DKD) and focal segmental glomerulosclerosis (FSGS). Pattern abundant clinical evidence suggests that alternative pathway activation also
recognition molecules, such as mannose binding lectin (MBL) and natural occurs directly on the capillary wall58. In aHUS, although the alternative pathway
IgM might recognize glycated proteins and activate the complement system. is regulated in the fluid phase, regulation on the surface of endothelial cells is
Complement regulation can also become impaired in these diseases, promoting impaired. GBM, glomerular basement membrane.

lectin pathways, and C3b is a component of the alternative pathway can also express complement proteins29,30, and this is often detected
C3 convertase (C3bBb). Although these proteins are synthesized as by RNA technologies31,32. Importantly, complement gene expression
soluble plasma proteins, their attachment on target surfaces focuses is not synonymous with activation per se, but local production of the
complement activation at these sites, including the kidney. Kidney cells substrate proteins might increase the degree of activation in the kidney,

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and also contributes to the systemic pool of complement proteins33. or lysis of target cells38. Within the kidney, full activation of the comple-
Recent work has also shown that complement proteins are involved ment cascade, which generates all of these fragments, has profound
in physiological processes that occur within cells (‘intracellular com- local and systemic effects.
plement’)34. The synthesis of complement proteins by cells within the
kidney, might therefore also have a role in non-canonical functions Complement regulation
beyond those discussed here. As outlined above, multiple mechanisms of complement activation
exist, each of which elicits downstream responses. To protect itself from
Complement effects uncontrolled complement activation, the body expresses regulatory
Several protein fragments generated during complement activation cell-surface and soluble proteins39 (Fig. 3). These regulators act at several
mediate physiological responses (Fig. 2). C3 goes through a sequential levels within the complement cascade. Some regulators control the
cleavage process, yielding C3b, iC3b and, eventually, C3d fragments. convertases — either by shortening the half-life of these complexes (decay
C3b is an active component of the C3 and C5 convertases, whereas acceleration) or by serving as cofactors for the cleavage of C3b or C4b by
iC3b and C3d are no longer enzymatically active. Leukocyte recep- the protease factor I (cofactor activity). Several circulating proteins block
tors can bind each of these C3 fragments specifically and mediate a activation of the classical and lectin pathways specifically. C4-binding
variety of downstream functions35. C3a and C5a (also known as ana- protein (C4bp), for example, controls the classical pathway C3 convertase
phylatoxins) are small soluble peptides released following the cleavage through decay acceleration and cofactor activity40. MAp44 (also known
of C3 and C5, respectively. Leukocytes and parenchymal cells express as MAP-1) is a specific inhibitor of the lectin pathway41. In addition, ana-
seven-transmembrane G protein coupled receptors for C3a and C5a. phylatoxins are rapidly cleaved and inactivated by carboxypeptidase N42,
C3a and C5a have potent pro-inflammatory effects but can also attenu- whereas CD59 prevents C5b–9 formation39.
ate inflammation in some settings, and can promote recovery from Factor H is a soluble glycoprotein that acts through decay accelera-
injury36,37. The larger fragment generated by C5 cleavage (C5b) is the initial tion and cofactor activity to control the alternative pathway in solution
component of a multimeric complex (C5b–9; also known as the mem- and on host tissues43. Although all kidney cells express more than one
brane attack complex), which can form pores in plasma membranes, type of complement regulator on their surface, factor H is particu-
allowing passage of ions across the membrane and causing activation larly important for controlling alternative pathway activation in the

Neutrophil B lymphocyte
CR3

3
CR2
iC3b C3d BCR
MBL and
Lectin saccharide
1 C3 C5
pathway
C2, C4 C3 C5
C1q and convertase convertase
Classical IgM or IgG C4bC2a C4bC2aC3b
pathway or C3bBb C3b or C3bBbC3b C5b
4
C2, C4 C6, C7, C8,
Amplification multiple C9
Alternative loop Platelet
pathway
C3a
C3, FB, FD
2
C5a

Endothelial
cells
C3aR 5

Mesangial C5b–9
cell C5aR

GBM

Podocytes

Slit diaphragm

Fig. 2 | Complement fragments mediate multiple downstream effects. The a receptor for C3d (complement receptor 2 (CR2)). Addition of a C3b molecule to
C3 convertase of the classical and lectin pathways — the C4bC2a complex — and the C3-convertases also creates a C5-convertase (4). The C5-convertases cleave
the C3-convertase of the alternative pathways — the C3bBb complex — cleave C5 into the C5a and C5b fragments. The biological functions of C5a, including
C3 into C3a and C3b fragments (1). C3a exerts many biological functions via its vasoactive and pro-inflammatory effects, are exerted through its receptor (C5aR).
receptor (C3aR), which is expressed on mesangial cells, podocytes, platelets and C5aR is expressed on neutrophils, mesangial cells and endothelial cells, among
leukocytes, among other cell types (2). As a component of the alternative pathway other cell types. C5b associates with C6, C7, C8 and multiple C9 molecules to
C3-convertase, C3b feeds into the amplification loop. C3b also undergoes further form C5b–9, also referred to as the membrane attack complex (MAC). C5b–9
cleavage, yielding iC3b and C3d (3). Myeloid cells express a receptor for iC3b creates a pore in cell membranes that can induce cell activation or lysis (5).
(complement receptor 3 (CR3)), and B cells and follicular dendritic cells express GBM, glomerular basement membrane; MBL, mannose binding lectin.

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glomerulus (Box 1). For example, congenital and acquired defects in FH-related
proteins FH
factor H function are strong risk factors for atypical haemolytic– Glycocalyx ?
CD55
uraemic syndrome (aHUS) and C3 glomerulopathy (C3G)44,45. The CD46
CD59
factor H-related proteins (FHRs) are a group of five structurally related
proteins that arose through duplication of the factor H gene (CFH)43.
Endothelial
Rather than inhibit complement activation, the FHRs are thought to cells
be positive regulators of the alternative pathway. Genetic variants GBM
of the CFHR genes are associated with the same kidney diseases as
Podocytes
factor H, possibly because the mutant proteins antagonize factor H
binding to kidney surfaces. Wild-type FHR proteins also seem to affect Slit
complement regulation or dysregulation within the kidney46,47. diaphragm

Complement-mediated kidney disease

C3G and aHUS are the prototypical complement-mediated kidney dis-
eases. The complement system is not simply a downstream mediator CR1
of inflammation in these conditions, but is the primary driver of kidney Fig. 3 | Complement regulators in the kidney. Multiple complement
injury. Both are ultra-rare orphan diseases caused by dysregulation regulatory proteins are expressed within the glomerular capillaries. Glomerular
and/or overactivation of the alternative pathway. However, the patho- endothelial cells express CD46, CD55 and CD59. CD46 is a transmembrane
physiology, clinical course and treatment of these diseases are distinct protein, whereas CD55 and CD59 are attached to the outer cell membrane by
(Table 1). aHUS is a form of TMA that occurs when endothelial damage glycosylphosphatidylinositol anchors. Podocytes express CD46, CD55, CD59,
in the microvasculature is perpetuated by alternative pathway activity as well as complement receptor-1 (CR1). Factor H (FH) is a soluble glycoprotein
on the capillary wall48. aHUS primarily involves the kidney endothelium produced in the liver and present at high concentrations in plasma; it comprises
20 repeating domains, some of which contribute to its regulatory ability, whereas
but extrarenal manifestations are common49. By contrast, C3G is pri-
others mediate binding to host surfaces. Control activation of the alternative
marily confined to glomeruli, although some patients develop partial
pathway on the endothelial glycocalyx and the glomerular basement membrane
lipodystrophy and macular drusen50.
(GBM) through factor H is likely crucial given that other complement regulators
Both aHUS and C3G are associated with congenital and acquired are not expressed at these locations. Similar to FH, FH-related proteins have
defects in the regulation of the alternative pathway, and the causes of repeating domains that mediate binding to surfaces. In contrast to the regulatory
these diseases are closely intertwined. Approximately 10% of children proteins, FH-related proteins might inhibit factor H binding and thus promote
with aHUS have autoantibodies to factor H that impair its regulatory activation of the alternative pathway in the kidney.
function on endothelial cells51. Most patients with C3G have auto­
antibodies, also termed nephritic factors, that bind to and stabilize
the C3 convertase52. In older patients, C3G is commonly associated
with co-existing monoclonal gammopathies53. Thus, although aHUS Glomerulonephritis associated with monoclonal
and C3G are not associated with glomerular immune complexes, gammopathies
both diseases are frequently associated with autoantibodies to Immunoglobulin or immunoglobulin fragments can deposit in the
complement proteins. glomeruli of patients with monoclonal gammopathies62,63. The heavy
aHUS and C3G are also associated with genetic variants of alter- chain CH2 constant region of immunoglobulin interacts with C1q to
native pathway regulators (CFH, CFI, CD46) and activating proteins activate the classical pathway and glomerular C3 is usually present
(C3 and CFB)54. The C3 and CFB variants tend to be gain-of-function when intact immunoglobulins are deposited, particularly in cases where
mutations that render the C3 convertases resistant to regulation. As a the clone is IgG3 (a classical pathway-activating isotype)63,64. However,
general rule, the genetic variants and autoantibodies associated with monoclonal gammopathies are often associated with C3G. The circu-
aHUS affect the ability of complement regulators to control activation lating paraprotein seems to activate the alternative pathway within
of the alternative pathway on endothelial cells44,55 (Fig. 1). By contrast, the glomerulus, despite the lack of prominent antibody or antibody
the genetic variants associated with C3G generally impair complement fragment deposition65. In one reported case, the paraprotein interfered
regulation in the fluid phase or on the glomerular basement membrane with the regulatory function of factor H66.
(GBM)56. However, these distinctions are not absolute. Patients with the
same genetic variant might develop either of these diseases, and some Immune complex-mediated MPGN
patients have first presented with C3G and later developed a TMA57. Membranoproliferative glomerulonephritis (MPGN) was originally
Notably, autoantibodies and genetic variants in genes associated with described based on the histological pattern seen by light microscopy,
the alternative pathway cause dysregulation throughout the body, but this classification has evolved over the past few years. Biopsy sam-
but the kidney is often the only affected organ58. ples with abundant C3 staining in the relative absence of glomerular
Given that aHUS and C3G are caused by uncontrolled activation of immune complexes are now classified as C3G, and affected patients
the alternative pathway, complement inhibitory drugs should be the often have molecular defects in the control of the alternative pathway67.
cornerstone of treatment (Fig. 4a). However, although clinical trials By contrast, biopsy samples with prominent glomerular immune com-
have established C5 inhibitors as the standard of care for aHUS59,60, plexes are classified as immune complex-mediated MPGN (IC-MPGN),
these drugs have not yet shown a clear benefit in C3G61. This relative where the immune complexes are presumed to trigger activation of
lack of efficacy in C3G might be due to a pathogenic role of upstream the classical pathway68. IC-MPGN and C3G are therefore regarded
complement fragments, such as C3a. Nevertheless, the efficacy as having distinct underlying pathological processes that manifest
of complement inhibitors in this disease remains uncertain. with similar light microscopic findings. However, the differentiation

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characteristics that make it susceptible to complement activation58.

Box 1 However, important differences exist in the roles of the complement
system in these diseases.

The factor H family of proteins Immune complex-mediated kidney diseases

The kidneys are a common site of immune complex deposition in
Factor H is an important regulator of the alternative pathway patients with autoimmune or chronic inflammatory diseases. Immune
that is primarily produced in the liver and circulates in plasma complexes can be detected in kidney biopsy samples by immunostain-
as a soluble protein. Several regions within factor H mediate ing the tissue for immunoglobulin (IgG, IgM, or IgA) and by electron
binding of the protein to C3 activation fragments and to anionic microscopy. A single C1q molecule binds to a cluster of six IgG mole­
glycosaminoglycans. This binding allows factor H to regulate cules, but it can also bind to a single IgM molecule that is bound to
activation of the alternative pathway in solution and on the antigen71. Generation of C4b and C3b downstream of classical path-
tissue surfaces to which it binds. Genetic variations in CFH and way activation and their covalent binding to target surfaces often
autoantibodies against factor H are among the strongest risk factors leads to co-deposition of immunoglobulin, C1q, C4 and C3 fragments
for atypical haemolytic–uraemic syndrome and C3 glomerulopathy, within glomeruli20,72.
which highlights the crucial role of this regulator in protecting
the kidney. Although other complement regulatory proteins Membranous nephropathy. Membranous nephropathy (MN) is char-
are expressed in the kidney, the endothelial glycocalyx and the acterized by the presence of subepithelial immune complex deposits
glomerular basement membrane are acellular surfaces that do not and co-deposited complement proteins73, although conflicting data
express intrinsic regulators and are probably dependent on factor H have created uncertainties regarding the role of the complement
from plasma. This limitation might explain the susceptibility of system. C3 fragments are detected in biopsy samples from almost
endothelial cells and the glomerular basement membrane to all patients with MN74. However, autoantibodies in MN are predomi-
alternative pathway-mediated inflammation in the setting of factor H nantly IgG475,76, which is an isotype that does not activate the classical
impairment. The factor H family of proteins also contains five pathway effectively77. Furthermore, studies have reported that C4d
factor H-related proteins (FHRs) that arose through duplication is often deposited in the absence of C1q74,78, suggesting that comple-
of CFH. The FHRs contain tissue binding regions similar to those of ment activation occurs through the lectin pathway. MBL molecules
factor H, but they do not have the capacity to inhibit activation bind to galactose-deficient glycan side-chains on anti-phospholipase
of the alternative pathway. Genetic variants in FHR genes are also A2 receptor (PLA2R) IgG4 autoantibodies, which could explain how
associated with atypical haemolytic–uraemic syndrome and C3 these autoantibodies engage the lectin pathway directly79. However,
glomerulopathy, indicating that the FHRs affect complement 5 patients with MN and a nearly complete deficiency of MBL have
regulation and activation in the same anatomical locations as also been reported, indicating that activation of the lectin pathway is
factor H. Current hypotheses suggest that FHRs block the protective not essential80. Complicating matters further, a patient with MN and
effect of factor H on glomerular surfaces, or promote alternative C4 deficiency has also been reported, suggesting that the alternative
pathway activation directly on tissues to which they have bound. pathway can have a role in the absence of activation of the classical or
Interestingly, although factor H and the FHRs are soluble plasma lectin pathway81.
proteins, molecular defects in these proteins often manifest with A 2023 study re-examined the presence of the classical and lectin
disease limited to the kidneys. These associations indicate that pathway convertase (C4b2a) and the alternative pathway (C3bBb) in
other complement regulatory proteins cannot compensate for MN biopsy samples using proximity ligation assays20. This study found
impairments in the function of factor H. activation of all three pathways in various biopsy samples. However,
contrary to previous reports, activation of the classical pathway was
also detected in all cases. The investigators found deposits of at least
one classical pathway-activating IgG isotype (that is, IgG1, IgG2 or IgG3)
of these diseases is not absolute. The pathological criterion for the and glomerular C1q in all biopsies, although detection of these proteins
diagnosis of C3G is glomerular C3 deposition that is two orders of sometimes required antigen retrieval20.
magnitude brighter than that of deposited immunoglobulin69. This Early studies in the passive Heymann Nephritis model of MN indi-
definition allows for some immune complex deposition in C3G, poten- cated that formation of C5b–9 on podocytes is an important media-
tially leading to misdiagnosis. The diagnosis might also be affected tor of injury82 but a clinical trial of C5 inhibition with eculizumab did
by a limited number of glomeruli sampled in a biopsy. Of note, many not show a significant benefit83. C3 activation fragments generated
patients with IC-MPGN have the same underlying defects in alternative upstream of C5 might also have a role in this disease. In support of this
pathway regulation as those found in patients with MPGN52,70. IC-MPGN hypothesis, immunostaining of biopsy samples from patients with MN
and C3G might therefore both be diseases of complement-mediated demonstrated that C3aR is upregulated on podocytes compared with
glomerular injury, with some cases being triggered by immune healthy individuals and disease controls84. The researchers also found
complex deposition. that exposure of podocytes in vitro to serum from patients with MN
caused morphological changes84. C3a blockade prevented these altera-
Complement as a downstream mechanism tions, thereby implicating C3a in disease pathogenesis. Altogether,
of kidney injury these preclinical and clinical studies indicate that, although activation
The complement system is secondarily activated in many kidney of the classical pathway seems to be dominant, which is consistent
diseases. The frequent involvement of this system in disparate con- with immune complexes as the primary cause of activation, all three
ditions suggests that the kidney has anatomical and biochemical complement activation pathways can be involved in MN and multiple

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downstream fragments contribute to injury. Consequently, even in at the level of C3 or C5, such as selective C5a blockade, should leave
this well-understood disease, the optimal approach to therapeutic the early classical pathway intact and might circumvent this problem.
complement inhibition remains to be determined. Preclinical studies also suggest that selective blockade of the alterna-
tive pathway maintains the protective effects of the classical pathway
Lupus nephritis. In lupus nephritis, autoantibodies bind to intrinsic while preventing the generation of downstream pro-inflammatory
kidney antigens as well as deposited antigens. Intra-renal complement fragments92,93.
activation is probably due to activation of the classical pathway by
deposited immune complexes. Paradoxically, the classical pathway Anti-glomerular basement membrane disease. Anti-GBM disease is
also protects the host from developing autoimmunity, and deficien- caused by autoantibodies against the non-collagenous-1 (NC1) domain
cies of classical pathway proteins (C1q, C1r, C1s, C2 or C4) are strong of type IV collagen in the GBM94. Patients with IgG1 autoantibodies
monogenic risk factors for developing systemic lupus erythematosus85. (complement activating) tend to develop kidney disease, whereas
Mechanistically, activation of the classical pathway facilitates rapid those with IgG4 autoantibodies (non-complement activating) do not95.
clearance of apoptotic cells, which prevents the development of auto- Although plasma C3 and C4 levels are not usually decreased, C1q and C4d
immunity against nuclear antigens86. However, once autoimmunity are deposited in glomeruli, consistent with classical pathway activation96.
develops, activation of the classical pathway within the glomerulus Complement-inhibiting agents are protective in preclinical mod-
triggers downstream inflammatory responses. els of anti-GBM disease, demonstrating that activation of complement
The clinical evidence that complement is activated in the kidneys on the GBM contributes to glomerular injury97. Therapy currently
of patients with active lupus nephritis is abundant. Decreases in plasma focuses on elimination of the pathogenic B cells and auto-antibodies
C4 levels can predict flares, which seem to coincide with a fall in but, even with treatment, many patients progress to kidney failure98.
C3 levels87. By contrast, complement activation fragments (such as iC3b Of note, even if plasmapheresis removes autoantibodies from the cir-
and C4d) are increased in the plasma of patients with systemic lupus culation, any antibodies already bound within the capillary wall might
erythematosus compared with healthy controls, and might be more continue to cause glomerular injury. Therefore, complement-inhibiting
sensitive and specific for active kidney disease than the level of intact drugs might, in theory, prevent glomerular injury while waiting for
C3 or C4, respectively88,89. Deposits of immune complexes, and of C1q, other interventions to reduce autoantibody levels. One case report
C4 and C3 fragments (also known as a ‘full house’ immunofluorescence indicated that C5 blockade was protective in two patients who had
pattern) are almost always seen in biopsy samples from patients with not responded to other treatments (specifically, glucocorticoids,
active kidney disease, confirming that activation occurs within the cyclophosphamide, rituximab and plasmapheresis), which supports
glomerulus72,90. a potential role for complement blockade in this disease99.
Although the complement system is activated in lupus nephri-
tis, whether complement blockade has a therapeutic role remains Other antibody-mediated glomerular diseases
uncertain. Complement inhibitors might reduce inflammatory injury of In some glomerular diseases, autoantibodies do not activate the clas-
the kidney whereas suppression of autoantibody production is not yet sical pathway within the glomerulus. However, evidence suggests that
controlled with other immunosuppressive agents. However, the role of the complement system still mediates kidney injury.
the classical pathway in preventing the development of autoimmunity
raises questions as to whether complement blockade might worsen IgA nephropathy. Although IgA does not activate the classical pathway,
the underlying disease91. Drugs that target the complement cascade C3 fragments are co-deposited with IgA in almost all biopsy samples of

Table 1 | Atypical haemolytic–uraemic syndrome and C3 glomerulopathy

Parameter aHUS203 C3G204

Clinical course Acute Chronic

Incidence 0.2–1.9/million/year205 1–3/million/year206

Associated infectious disease Shiga toxin-producing Escherichia coli infection associated with Post-infectious glomerulonephritis
haemolytic–uraemic syndrome

Complement activation phase Endothelial cell and/or glycocalyx Fluid phase and/or glomerular basement membrane

Triggers Autoimmunity, transplantation, pregnancy, infections, drugs and Infection65,208

metabolic disease207

Kidney failure 60–70% without complement inhibition; 10–15% with complement 50% at 10 years67
inhibition203,209

Post-transplant recurrence Variable; depends on genetic risk factors210 Very high204

Extrarenal manifestations Systemic thrombotic microangiopathy; retinal drusen are rare Partial lipodystrophy211, retinal drusen212

C3 levels Low in 30–50% of patients213 Low in up to 75% of patients67,214

Acquired drivers Anti-factor H autoantibodies 215

Nephritic factors216, anti-factor H autoantibodies215,
monoclonal immunoglobulin53,217
aHUS, atypical haemolytic–uraemic syndrome; C3G, C3 glomerulopathy.

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a Complement-mediated b Complement as a downstream effector of antibody-mediated disease

disease
• Cyclophosphamide • Calcineurin inhibitors
• Mycophenolate mofetil • Rituximab

Loss of tolerance and autoimmunity

MHC
Complement class II TCR Complement
inhibitor Glucocorticoids inhibitors
Naive CD4
T cell
Non-complement mediated Complement mediated

CD86 CD28 Self-reactive

Mature DC C3a or C5a
antibody
STOP
C3a Complement
and C5a B cell C3b, iC3b
activation
and C3d
C3b, iC3b Damaged
Complement and C3d or activated C5b–9
activation endothelium
C5b–9
Effector Cytotoxic
CD4 T cell CD8 T cell

Cytokine Macrophage
GBM Slit diaphragm Podocyte
release Haematuria
Endothelial cells Podocyte damage
Proteinuria

Fig. 4 | Complement-inhibiting drugs for the treatment of kidney diseases. activation of the adaptive immune response; pro-inflammatory CD4 T cells,
Complement activation generates C3a, C3b,iC3b,C3d, C5a and C5b–9. cytotoxic T cells, macrophages and cytokines all contribute to tissue injury.
These fragments have multiple pro-inflammatory effects and are sufficient to Consequently, complement inhibitors might only block a subset of downstream
cause glomerular injury. a, Complement fragments are the primary drivers of mediators of injury and would probably need to be used in combination with
disease in atypical haemolytic–uraemic syndrome and C3 glomerulopathy. In drugs that block the primary autoimmune response. However, standard immuno­
these diseases, complement-inhibiting drugs block the pathological downstream suppressive drugs can take weeks or months to reduce kidney inflammation,
effects of complement activation. b, In antibody-mediated kidney diseases, and complement-inhibiting drugs might rapidly suppress kidney injury in
loss of tolerance enables the production of self-reactive antibodies. These the period before those drugs take effect. In addition, complement inhibition
autoantibodies can form immune complexes and generate pro-inflammatory might also modulate the primary adaptive immune response that causes
complement fragments. These inflammatory mediators can contribute to the autoimmunity.

patients with IgA nephropathy (IgAN)100. Furthermore, most patients The detection of glomerular C3 deposits in the absence of C4d in
do not have hypocomplementaemia, but those with decreased levels of many cases of IgAN, and the detection of Bb and properdin, also sug-
C3 have worse outcomes than patients with C3 levels within the normal gest an important role for the alternative pathway110,111. Additionally,
range101. The mechanism by which complement is activated in IgAN is a large genome-wide association study found that a relatively com-
unclear, but IgA1 can activate the alternative pathway directly in vitro102. mon deletion of genes for two of the FHRs (CFHR3 and CHFR1)112 is
Analysis of the circulating and deposited IgA1 has also revealed that protective against development of IgAN; this correlation was con-
the O-linked glycans in the hinge region of the molecule are galac- firmed in follow-up studies113,114. FHR1 and FHR3 can antagonize factor
tose deficient103. These modified glycans are targeted by IgA and IgG H-dependent regulation of the alternative pathway. Absence of these
autoantibodies104, and glomerular immune deposits contain a mixture proteins might therefore improve control of the alternative pathway
of galactose-deficient IgA1 as well as autoantibodies105. Complement and protect against disease development. Conversely, FHR5 deposits
activation could therefore be caused by the IgA1 deposited in the are seen in the glomeruli of patients with IgAN115,116, and higher plasma
glomeruli and/or the concomitant IgG autoantibodies. levels of FHR1 and FHR5 are associated with a worse prognosis47,117.
Histological evidence suggests that activation of the classical CFHR5 mutations are also associated with the risk of developing IgAN,
and lectin pathways occurs in subsets of patients with IgAN. C4d is possibly because the variants competitively inhibit the binding of
seen in >30% of biopsies106, whereas C1q deposits are less frequent107. factor H118. Together, these findings suggest a crucial disease-causing
Glomerular MBL is also seen in ~25% of cases and correlates with C4d role for the alternative pathway in IgAN, even if complement activa-
deposition19. The detection of these proteins in the glomeruli cor- tion is initially triggered through the classical or lectin pathways in
relates with a worse prognosis, supporting a pathogenic role for some patients.
complement19,106–109. Of note, although proteins from the classical
and lectin pathways are only detected in subsets of patients with IgAN, Anti-neutrophil cytoplasmic antibody-associated vasculitis.
antigen retrieval might reveal a greater prevalence for these proteins, Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculi-
as shown in MN20. tis (AAV) is an immunoglobulin-mediated disease that commonly
MBL can bind to galactose-deficient IgA1, similar to what was affects the glomerular capillaries. However, immunoglobulin and
shown for galactose-deficient IgG4 autoantibodies in MN79. MBL complement are only sparsely deposited in the glomeruli of affected
might also bind to neoepitopes displayed on injured glomerular cells. patients119. Experiments using a mouse model of AAV showed that mice

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with a genetic deletion of Cfb (necessary for activation of the alter- Glomerular diseases not associated with antibodies
native pathway) were protected from injury, whereas deletion of C4 Kidney biopsy samples are frequently immunostained for C3 and evi-
(necessary for activation of the classical and lectin pathways) was not dence suggests that complement is activated in glomerular diseases
protective120. These preclinical studies were surprising because the dis- not traditionally thought of as immune mediated.
ease is antibody-mediated, which would suggest complement activa-
tion through the classical pathway. Furthermore, complement deposits Diabetic kidney disease. Patients with diabetes might have kidney dis-
are prominent neither in the glomeruli of affected patients nor in the ease of any aetiology, but diabetic kidney disease (DKD) is the leading
mouse model120. C5-deficient mice were also protected from injury, cause of CKD and kidney failure worldwide. Deposition of complement
implicating either C5a or C5b–9 in disease pathogenesis 120. proteins in the glomeruli of patients with DKD is associated with worse
A subsequent study showed that deficiency or pharmacological inhi- outcomes130,131, but how complement is activated or whether it has a
bition of C5aR1 was protective, whereas mice deficient in C6, and pathological role remains unknown. Two mechanisms linking comple-
thus unable to form C5b–9, were not protected121. Collectively, these ment and DKD have been proposed — activation of the lectin pathway
preclinical studies indicate that complement activation in AAV pri- by glycated proteins and deregulation of the complement system
marily involves the alternative pathway, and that glomerular injury is owing to a glycation-induced impairment of complement regulators.
mediated by C5a. MBL binds to altered glycans and activates complement in vitro132
Although AAV is often described as ‘pauci-immune’, one study and might therefore bind to glycoproteins altered by the hypergly-
noted that immunoglobulin and complement proteins can be caemic state (Fig. 1). Several animal133–135 and human136,137 studies
detected in most biopsy samples122. Furthermore, pathogenic comple- also demonstrated increased activity of the lectin pathway in DKD.
ment activation might occur outside of the kidney. The original study Collectin-11, which is a lectin pathway activator that is important
using the AAV mouse model demonstrated that binding of ANCA in acute kidney injury (AKI; see below) is also elevated in plasma of
(either anti-proteinase 3 (PR3) or anti-myeloperoxidase antibodies) to patients with diabetes and microalbuminuria compared with plasma
activated neutrophils caused the cells to release an unidentified fac- levels of patients with diabetes and normoalbuminuria138. These obser-
tor that triggers activation of complement in serum120. Complement vations potentially represent downstream mechanisms of activation
activation might therefore occur on or near the neutrophils, rather of the lectin pathway in affected kidneys.
than directly on the glomerular capillary wall. Binding of C5a to C5aR1 Interesting experiments showed that hyperglycaemia can impair
on neutrophils induces the translocation of PR3 and myeloperoxidase the function of complement regulatory proteins directly. Chronic
to the neutrophil surface, thereby increasing the expression of ANCA hyperglycaemia correlates with urine levels of glycated soluble CD59,
ligands on the cells. C5a might therefore potentiate the action of which is functionally less effective at controlling C5b–9 formation
ANCA, which might, in turn, lead to complement activation through than the non-glycated form139,140. This effect might mechanistically link
their effects on neutrophils (Fig. 1). AAV is not usually associated with hyperglycaemia with acquired impairments of complement regulation.
low C3 and C4 levels, but one study found that patients with active Increased levels of glycated soluble CD59 in plasma were also reported
disease had elevated plasma and urine C5a levels compared with as a sensitive and specific biomarker for gestational diabetes141.
patients in remission and healthy individuals123. Analysis of plasma Notably, CD59 is ordinarily linked to the surface of cells through a
and urine from patients with active AAV also revealed that levels of Bb glycosylphosphatidylinositol anchor, but the significance of increased
(indicative of activation of the alternative pathway) were higher plasma levels of the protein is unclear. Moreover, in a mouse model of
in patients with active disease than in those in remission124,125. The DKD, tissue-specific deletion of CD55 (another cell surface complement
same study reported deposition of Bb in the glomeruli, indicating regulatory protein) in podocytes was associated with exacerbated kid-
that some activation of the alternative pathway might occur within ney disease142, highlighting the importance of adequate complement
the kidney124. regulation for protecting the diabetic glomerulus. Genetic variants in
The C5aR1 antagonist avacopan has now been tested in several factor H are also risk factors for the development of kidney and cardio-
clinical trials of patients with AAV126,127. Standard treatment of AAV vascular complications in patients with diabetes, presumably owing to
involves either cyclophosphamide or rituximab in combination with differences in the inhibitory function of the variants143.
glucocorticoids128,129. In a phase III study, patients were randomly
assigned to cyclophosphamide or rituximab in combination with Focal segmental glomerulosclerosis. Focal segmental glomeru-
either prednisone (tapered over 21 weeks) or avacopan (continued losclerosis (FSGS) is a podocytopathy144. Inflammatory changes are
for 52 weeks)126. Compared with standard treatment plus pred- not usually seen in the glomeruli by light microscopy nor are immune
nisone, cyclophosphamide or rituximab combined with avacopan complexes typically detected through electron microscopy. Although
was non-inferior in inducing remission by 26 weeks and sustained immunostaining often reveals glomerular deposits of IgM and C3,
remission in the avacopan group was greater at 52 weeks. Importantly, especially in sclerotic areas145,146, these findings have been ascribed to
patients treated with C5a blockade received significantly fewer glu- passive trapping of plasma IgM and C3 in the damaged tissue. However,
cocorticoids over the course of the study and, accordingly, had fewer preclinical and clinical studies showed that the deposited IgM activates
glucocorticoid-associated toxicities than those receiving standard the classical pathway146,147. Accordingly, glomerular C4d positivity was
treatment. Based on these results, avacopan has been approved in the reported in 73% of kidney tissue samples from patients with FSGS com-
USA, Canada and Europe as an adjunct therapy in AAV. This approval pared with only 10% of samples from healthy individuals148. Glomerular
is a success story for the use of animal models to identify and validate C4d colocalized with C1q but not MBL, indicating that activation likely
new treatments for human disease. Nevertheless, the mechanisms occurs through the classical pathway148. Complement activation frag-
by which C5a contributes to kidney injury are incompletely under- ments, including C4a and C4d, are also increased in urine and plasma
stood. For example, whether C5a acts within the kidney or directly on of patients with FSGS compared with healthy individuals and disease
neutrophils remains unclear. controls, providing further evidence of activation of the classical

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pathway149,150. Moreover, CD55 expression is lower in glomeruli of can also be detected within the cysts and in the urine of patients
patients with FSGS than in those of healthy controls142, which might with PKD, suggesting that similar processes might occur in human
potentiate complement activation, as discussed above for DKD (Fig. 1). disease164. Currently, no active clinical trials are testing the effect of
Immunoglobulin deposition and complement activation complement-inhibiting drugs in PKD.
are probably downstream events in FSGS that occur after injury
neoepitopes have been generated and complement regulation Susceptibility of the kidney to complement-
has become impaired. The glomerular immune deposits observed mediated injury
in FSGS might therefore be markers, rather than causes, of injury. As outlined above, the complement system is activated in kidney dis-
Nevertheless, complement-deficient mice are protected in a model of eases of widely differing aetiologies, suggesting that the balance of
adriamycin-induced podocyte injury151,152 and glomerular complement complement regulation or activation is easily disrupted in this organ.
deposits are associated with worse outcomes in patients with FSGS145. However, many differences exist between the microenvironment in
Therapeutic complement inhibition might therefore be an effective the glomerulus and that of the tubulointerstitium.
method of attenuating disease. Glomeruli are ‘inward-facing’ and are continually exposed to
high concentrations of complement proteins and immune complexes
C1q nephropathy. C1q nephropathy is defined by intense glomerular that are generated elsewhere in the body. Consequently, adequate
C1q staining. However, unlike in C3G, a defined cut-off of minimal complement regulation is probably crucial at this location to protect
intensity has not been specified and co-deposition of IgM, IgG or C3 is the kidney from the constant influx of these proteins. All cell-surface
frequent153,154. C1q deposits do not always correlate with immunoglobu- complement regulators are expressed on resident glomerular cells165
lin or C3 levels153, and whether these C1q deposits are an indicator of (Fig. 3). Furthermore, expression of these regulators increases in some
activation of the classical pathway remains unclear. By light micros- glomerular diseases, possibly as a protective response to complement
copy, the glomeruli usually have patterns of injury that are character- activation166,167. Nevertheless, complement regulation in the glomeru-
istic of minimal change disease or FSGS, although some patients have lus is clearly inadequate to prevent its activation in many glomerular
proliferative glomerulonephritis153,154. One study of children with mini- diseases. Perhaps a threshold of immune complex abundance exists,
mal change disease reported that C1q positivity was associated with beyond which these protective mechanisms are overwhelmed, or
more frequent relapses but found no differences in kidney outcomes155. immune complexes might become more pathogenic when a ‘second hit’
impairs local complement regulation. In contrast to glomerular cells,
Tubulointerstitial kidney diseases the GBM is fully dependent on soluble complement regulators, such as
The complement system is activated in several tubulointerstitial dis- factor H58. Consequently, although the GBM is susceptible to congenital
eases. The mechanisms and localization of complement activation in or acquired defects in factor H function, the availability of factor H to
these diseases suggests that activation in the tubulointerstitium occurs protect the GBM is probably not affected by glomerular cell injury.
independently of that in the glomerulus. In contrast to the microenvironment in the glomerulus, tubular
epithelial cells actively promote complement activation in the setting
Acute kidney injury. Much of the mechanistic data about complement of injury. CD46 is the main regulator expressed on tubular epithelial
in AKI comes from animal models of ischaemia–reperfusion injury. cells165, but several types of injury are associated with a reduction in
Studies in mice showed that the alternative pathway is activated in the complement regulation on the surface of these cells157,168. Moreover,
post-ischaemic tubulointerstitium156. Local production of complement tubular epithelial cells can synthesize C3 protein and lectin pathway
proteins increases after ischaemia, accompanied by an acquired loss of components (collectin-11 and l-fucose) that amplify local activation
complement regulation in the injured tubules157. A 2016 study reported a further169,170. Given that tubular epithelial cells are a ‘barrier’ epithelium,
mechanism by which the lectin pathway is activated in the kidney follow- these mechanisms that facilitate local complement activation might
ing ischaemia158. Both collectin-11 and its ligand l-fucose are produced have evolved as a defence against urinary pathogens.
by stressed tubular epithelial cells. Secreted collectin-11 can bind l-
fucose displayed on the outer cell membrane and trigger activation Therapeutic options for targeting the complement
of the lectin pathway. The same mechanism of lectin pathway activa- cascade
tion occurs on tubular epithelial cells injured by myoglobin159. Thus, Eculizumab was the first anti-complement therapeutic to be approved
this process might be a common pathway by which complement is by the FDA for the treatment of a kidney disease (specifically, aHUS) in
activated following tubular injury. 2011. Additional anti-complement drugs have since been approved for
Biomarker evidence also suggests that complement activation non-kidney diseases or are in the late stages of clinical development171–173
occurs in patients with AKI. Urinary factor B levels prior to surgery pre- (Box 2 and Table 2). Multiple anti-complement drugs with potential
dict the development of AKI in patients undergoing cardiac surgery160. applications in nephrology might therefore soon become available.
After surgery, urinary levels of the Ba fragment predict the develop- These drugs are categorically different from other types of immunosup-
ment of AKI161. Of note, C3d is deposited in the tubulointerstitium of pressive drugs and are likely to be beneficial in some kidney diseases
patients with AKI in a pattern similar to that seen in AKI rodent models2. for which other immunomodulatory drugs are ineffective (Fig. 4).
A clinical trial of ravulizumab (an anti-C5 antibody) for prevention of Complement inhibitors might also be useful in combination with
AKI in patients undergoing non-urgent cardiac surgery is ongoing immunosuppressive drugs for antibody-mediated diseases, providing a
(ClinicalTrials.gov NCT05746559). rapid anti-inflammatory effect that is not achieved by cytotoxic agents.
Interestingly, despite kidney transplant recipients being maintained
Polycystic kidney disease. In a mouse model of autosomal-recessive on multiple immunosuppressive medications, complement activation
polycystic kidney disease (PKD), C3 was strongly upregulated in the still contributes to kidney allograft injury in many settings, including
kidneys162 and C3−/− mice had attenuated cystogenesis163. C3 fragments ischaemia–reperfusion injury and antibody-mediated rejection174.

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This observation highlights the limited ability of these drugs to prevent

complement activation in the kidney. Box 2
Selection of anti-complement therapeutics
Currently available drugs can block complement activation all along the Complement-inhibiting drugs
cascade, including agents that selectively target the classical171, lectin175
or alternative pathways176 (Box 2). Drugs that prevent the activation of for kidney disease
C3, such as pegcetacoplan and AMY-101, block activation through all
three pathways and suppress generation of all downstream activation Complement-inhibiting drugs block an arm of the immune system
fragments (C3a, C3b, C5a and C5b–9)172,177. By contrast, eculizumab and that is not regulated by other immunosuppressive drugs. Five
other drugs directed at C5 prevent the formation of C5a and C5b–9 complement-inhibiting drugs have been approved by the FDA
while the proximal complement pathway remains intact. Drugs that for clinical use: eculizumab, ravulizumab, sutimlimab, avacopan
narrowly inhibit selected components of the complement system might and pegcetacoplan. The most extensive clinical experience is
have fewer side-effects than drugs that block activation more broadly. with eculizumab, which blocks the complement cascade at the
However, complement activation in several kidney diseases seems level of C5. This drug was approved for treatment of atypical
to occur through more than one activation pathway and a restricted haemolytic–uraemic syndrome in 2011, but has been used
approach in those diseases might therefore be ineffective. off-label to treat other kidney diseases, including catastrophic
Anti-complement drugs will be particularly useful for treating antiphospholipid syndrome, lupus nephritis, IgA nephropathy and
kidney diseases caused or exacerbated by activation of the lectin or anti-glomerular basement membrane disease. Ravulizumab also
alternative pathways, as conventional immunosuppressive drugs do blocks the cleavage of C5 but only needs to be re-dosed every
not block the protein–ligand interactions that activate these pathways. 8 weeks, in contrast to every 2 weeks for eculizumab. Avacopan
Complement-inhibiting drugs might therefore be used as monothera- blocks C5a receptor 1 (C5aR1) signalling and was approved for
pies for conditions in which autoantibodies are not the key drivers of the treatment of antineutrophil cytoplasmic antibody-associated
disease. For diseases in which the lectin or alternative pathways are vasculitis in 2021. Pegcetacoplan and sutimlimab have been
activated downstream of glomerular injury, as might be the case for approved for non-renal indications but might be useful for treating
DKD and FSGS, complement inhibition could prevent secondary drivers kidney disease. Pegcetacoplan blocks complement activation at
of disease progression. the level of C3 and should be effective regardless of the pathway
By contrast, in antibody-mediated diseases, complement- by which the complement cascade is activated. This drug was
inhibiting drugs might be used as adjuncts to drugs that suppress the originally tested in paroxysmal nocturnal haemoglobinuria172 and is
autoimmune response (Fig. 4b). Of note, anti-T cell and B cell agents, currently being tested in patients with C3 glomerulopathy and
such as cyclophosphamide or rituximab, do not suppress autoantibody immune complex membranoproliferative glomerulonephritis
production in all patients178,179. Moreover, even when a treatment sup- (NCT05067127). Sutimlimab targets C1s and blocks activation
presses the production of new antibodies, pre-existing immune com- of the classical pathway. It was initially tested as a treatment for
plexes that are deposited in tissues might persist for weeks or months. cold agglutinin disease171. Although sutimlimab has not been
Complement-inhibiting drugs could thus reduce the pathological tested in kidney disease, it might be effective in the treatment
effects of those immune complexes until they are cleared. of immune complex-mediated glomerulonephritis. Purified C1
The current therapeutic approach to many types of glomerulo- esterase inhibitor is also used to treat patients with deficiency
nephritis — including lupus nephritis, AAV and MN — involves com- of this enzyme, and some evidence suggests that it might
binations of cytotoxic drugs with glucocorticoids. Although strong suppress activation of the classical pathway. Many additional
interest exists in minimizing the cumulative dose of glucocorticoids complement-targeting drugs are currently in clinical trials,
used in these diseases, given that they are a major cause of patient including drugs that selectively block activation of the alternative
morbidity180,181, the rapid anti-inflammatory and disease-modifying or lectin pathways175,218 (see also Table 2). In addition, several
effects of these therapies are still considered essential. As in AAV126, molecular entities have been developed as complement inhibitors,
complement inhibition might enable the reduction or elimination including monoclonal antibodies, small molecules and nucleic
of steroids, thereby reducing treatment-related side effects. More- acid-based therapies219. Among these drugs, some require
over, selective inhibitors such as avacopan probably have a better intravenous administration, whereas others can be administered
side-effects profile than more broadly acting inhibitors and might subcutaneously or orally. This expanding catalogue of therapeutic
therefore be good steroid substitutes with fewer side effects. However, agents offers the possibility of targeting the complement system
whether C5a has a similar role in other glomerular diseases to that in at different points in the cascade, and activation can be blocked
AAV remains to be determined. for short or prolonged periods. These therapeutic options
Several independent studies showed that podocytes express C3aR might eventually allow clinicians to use drugs that block the
and that C3a contributes to proteinuria via its direct effects on the disease-specific mechanisms of complement activation effectively,
podocyte84,142,182. C3a might therefore be a common mediator of pro- and to choose therapies with different durations of action.
teinuria in diverse settings, including immune complex-driven disease,
glomerulosclerosis and DKD84,142,182. As discussed above, structural
glomerular injury might disrupt local complement regulation across a to be immune mediated. Similar to C5a antagonists, drugs that selec-
range of diseases and permit secondary complement activation in the tively target C3a would be expected to have a favourable side-effects
glomerulus. C3aR antagonists might therefore protect podocytes in profile. Unfortunately, to our knowledge, no such drugs are currently
many diseases, including diseases that are not traditionally considered in clinical development.

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Table 2 | Complement inhibitors in kidney disease

Target Drug Disease Clinical trial #

Alternative pathway
Factor B Iptacopan aHUS NCT04889430, NCT05795140
C3G and/or post-Tx recurrence of C3G NCT03955445, NCT03832114c, NCT04817618
IC-MPGN NCT05755386
LN NCT05268289
IgAN NCT03373461c, NCT04557462, NCT04578834
IONI-FB-LRx IgAN NCT04014335
Factor D Danicopan (ALXN2040) C3G, IC-MPGN NCT03124368c, NCT03369236c, NCT03459443c
Vemircopan (ALXN2050) IgAN, LN NCT05097989
C3 Pegcetacoplan TA-TMA NCT05148299
C3G, IC-MPGN NCT05067127, NCT05809531
Post-Tx recurrence of C3G or IC-MPGN NCT04572854
Classical pathway
C1s Sutimlimab (BIVV009)a Cold agglutinin disease NCT05132127c, NCT03347396c, NCT03347422c
C1INH Cinryze, Berinert, Ruconest AMR NCT02547220c, NCT03221842c, NCT01147302c,
NCT01134510c
Ischaemia–reperfusion injury, delayed graft function in NCT02134314c, NCT04696146
kidney transplantation
Lectin pathway
MASP2 Narsoplimab (OMS721) TA-TMA NCT05855083
C3G, IgAN, LN, MN NCT02682407
IgAN NCT03608033
TMA including aHUS NCT02222545c, NCT03205995
Terminal pathway
C5 Eculizumab AMR NCT01399593c
STEC-HUS NCT01410916c
Delayed graft function NCT02145182c
aHUS NCT01193348c, NCT05726916
Ravulizumab (ALXN1210) TMA NCT04743804
TA-TMA NCT04543591, NCT04557735
IgAN, LN NCT04564339
aHUS NCT03131219c
Acute kidney injury following cardiac surgery NCT05746559
Nomacopan (rVA576) b
TA-TMA NCT04784455
IgAN NCT03841448
C5a Vilobelimab ANCA-associated vasculitis NCT03895801c
C5aR1 Avacopan C3G NCT03301467c
ANCA-associated vasculitis NCT02994927c, NCT01363388c, NCT02222155c
IgAN NCT02384317c
aHUS, atypical haemolytic uraemic syndrome; AMR, antibody-mediated rejection; ANCA, antineutrophil cytoplasmic antibody; C3G, C3 glomerulopathy; IC-MPGN, immune complex
membranoproliferative glomerulonephritis; IgAN, immunoglobulin A nephropathy; LN, lupus nephritis; MN, membranous nephropathy; STEC-HUS, Shiga toxin-producing Escherichia coli
infection-associated haemolytic–uraemic syndrome; TA-TMA, transplant-associated thrombotic microangiopathy; TMA, thrombotic microangiopathy; Tx, transplantation. aSutimlimab has not
yet been tested in kidney diseases. bNomacopan inhibits both C5 and leukotriene B4. cCompleted or with reported results.

In addition to mediating inflammation within the kidney directly, and T cell polarization184,185. Given this crosstalk between the comple-
complement activation fragments also have several immunomodula- ment system and the adaptive immune system, anti-complement
tory effects. C3 fragments serve as adjuvants, lower the threshold for therapies might not only affect the innate immune pathways but also
B cell activation183 and affect the activation of T cells by dendritic cells attenuate the upstream autoimmune response that is the primary cause

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of some diseases. Nevertheless, the effect of complement inhibitors on for persistent production of C5b–9 in these patients while they were
autoimmunity, particularly in the context of other immunosuppressive receiving eculizumab is unknown.
drugs, remains to be confirmed in clinical studies.
Immunostaining of kidney biopsies for complement proteins
The risks of complement blockade Plasma complement biomarkers are not specific indicators of com-
The primary risk of complement-inhibiting drugs is probably the plement activation in the kidney. However, immunostaining for
increased susceptibility to infection. The overall risk of complement tissue-bound C3 and C4 fragments can provide evidence of comple-
blockade depends on where in the cascade the drug works, the dura- ment activation within the kidney. Moreover, comparison of C3 and C4
tion of treatment, and other clinical characteristics that might predis- deposits indicates which activation pathways are involved. In kidney
pose a patient to infection186. The risk of infection will presumably be transplant recipients, detection of C4d in the peritubular capillaries
even greater when complement inhibitors are combined with other is one of the criteria for diagnosing antibody-mediated rejection4.
immunosuppressive drugs. Of note, complement proteins are fre- Although not covalently bound within the kidney, many other com-
quently consumed in autoimmune disease, which already increases plement proteins can also be detected within glomerular deposits,
the risk of infection in affected patients and might offset the additive including C1q. In an immune complex-mediated disease, deposited
risk of a complement inhibitor187. These considerations must also immunoglobulin activates the classical pathway and is co-deposited with
be weighed against the overall prognosis of the underlying disease C1q, C4d and C3 fragments68,193,194. By contrast, the detection of C3
and the availability of other treatments. Vaccination and the use of deposits in the relative absence of immunoglobulin or C4d suggests
prophylactic antibiotics will probably be essential to mitigate the risk activation of the alternative pathway and is the basis of the C3G
of infection. Moreover, as mentioned above, congenital deficiency of diagnosis48,194. Of note, although detection of complement proteins
classical pathway proteins increases the risk of developing autoim- in the kidney provides useful clinical information, the first two kidney
mune disease and whether therapeutic blockade poses the same risk diseases for which complement inhibitors have been approved — aHUS
remains unknown. As new anti-complement drugs enter the clinic, and AAV — are not characterized by prominent complement deposition
it will be important to determine whether they cause or exacerbate in kidney biopsy samples.
autoimmunity.
Evidence for complement dysregulation
Complement biomarkers Given that the complement cascade requires a delicate balance between
Complement system assessment is currently part of the standard clini- activating and regulatory molecules, acquired or genetic defects that
cal evaluation for many kidney diseases188. Complement proteins and disrupt this balance are important drivers of disease. Molecular studies
fragments are measured in plasma, and kidney biopsy samples are have shown that variants in genes involved in the alternative pathway
routinely immunostained for C3c, C4d and C1q. These analyses help to are strong risk factors for the development of aHUS and C3G45,56,70,195,196.
establish the diagnoses of some kidney diseases and provide informa- Several clinical laboratories now provide genetic analyses for patients
tion about disease activity. Unfortunately, testing is not yet capable of with kidney disease. Genetic studies are not necessary for the diagnosis
accurately identifying which patients will benefit from treatment with of aHUS, but identification of a complement gene variant can provide
complement-inhibiting drugs188. useful prognostic information and aid in clinical decision making192,197.
Acquired causes of complement dysregulation include production
Measurement of complement proteins and fragments of autoantibodies that block the function of factor H51, or production of
Several kidney diseases are associated with decreased levels of C3 and endogenous proteins that antagonize factor H198. Nonetheless, even in
C4, including lupus nephritis, post-infectious glomerulonephritis, patients with these molecular impairments, disease is often triggered
cryoglobulinaemia, C3G and IC-MPGN52,87,189. Decreased levels of C3 by an infection199. This observation suggests that an additional ‘hit’ is
and C4 are interpreted as indicators of disease activity. However, in needed. Infections might increase production of complement proteins
other diseases, complement activation in the kidney causes damage by the liver as they are acute phase reactants. Infections might also alter
without depleting circulating levels of complement proteins. Even in the expression of complement regulatory proteins by injured cells, or
lupus nephritis, which is well known for its association with hypocom- induce the release of complement-activating extracellular vesicles200.
plementaemia, these serological tests do not accurately reflect disease Notably, heterozygous defects in factor H are also strong risk factors
activity within the kidney87. for aHUS. Moreover, once a disease flare has been triggered, plasma
Levels of the complement protein fragments that are released exchange is often insufficient to stop the pathological process49. These
as complement proteins are cleaved and consumed might be a more acquired imbalances in activation or regulation might therefore be
sensitive indicator of complement activation than assessment of C3 irreversible and cannot be attenuated by restoring normal levels of
and C4, and complement fragments have been explored as biomarkers functioning factor H.
of kidney disease88. In patients with MN, urinary C5b–9 levels seem to
correlate with ongoing immune complex formation in the glomerulus Conclusions
and might therefore serve as markers of immunological activity190,191. The kidney is uniquely susceptible to pathological complement acti-
The measurement of complement activation fragments is perhaps vation and abundant clinical evidence suggests that complement is
most useful in aHUS, where tests to monitor complement activity could pathogenic in diseases of widely different aetiologies. Uncontrolled
be used to guide treatment with complement inhibitors. Plasma C5b–9 activation of the alternative pathway is the primary driver of aHUS
levels might be particularly useful for monitoring the use of C5 inhibi- and C3G. The complement system is also activated by immunoglobu-
tors, which block C5b–9 formation. For example, in a study of patients lin and certain pattern recognition molecules, including MBL. These
with aHUS in whom eculizumab was discontinued, elevated C5b–9 complement-activating proteins bind to targets expressed in the
levels at the time of discontinuation predicted relapse192. The reason injured kidney. Importantly, complement regulation is frequently

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