Anti-Complement Therapy for Glomerular Diseases Andrew S. Bomback A major shift in our understanding of glomerular diseases is the focus on which components of the complement pathway are involved in mediating kidney injury. For example, the membranoproliferative glomerulonephritis lesion is no longer classified solely by ultrastructural findings on biopsy and is now divided into immune-complex-mediated lesions vs complementmediated lesions. In turn, this emphasis on complement leads to interest in therapies that target complement as potential disease-modifying agents. Eculizumab, the first available anti-complement therapy, blocks at the level of C5 and has revolutionized the treatment of atypical hemolytic uremic syndrome. Whether this agent will work equally well for the far more heterogeneous entities of C3 glomerulonephritis and dense deposit disease remains unclear. Instead, newer agents that target C3 may turn out to be the most effective and specific therapy for these C3 glomerulopathies. Q 2014 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Eculizumab, C3 glomerulopathies, Atypical hemolytic uremic syndrome, Complement, Anti-neutrophil cytoplasmic autoantibody

Introduction The last decade has ushered in a renewed focus on the role of complement and, specifically, abnormalities in the alternative complement pathway in the pathogenesis of glomerular diseases. Lesions such as membranoproliferative glomerulonephritis (MPGN) have undergone a major reclassification into immune-complex-mediated vs complement-mediated disease, and the advent of anticomplement therapy has drastically altered the treatment paradigm of atypical hemolytic uremic syndrome (aHUS). The ability to selectively target components of the complement pathway offers unique avenues to change the natural history of glomerular diseases, but it also may be associated with unforeseen consequences, including unintended infectious adverse events, stimulation of earlier components of the complement pathway, and the potential need for lifelong therapy. This review surveys current data on the role of complement in various glomerular lesions and the progress, to date, in studying anti-complement therapies in these diseases.

Immune-Complex-Mediated Glomerulonephritis vs Complement-Mediated Glomerulonephritis The complement system is divided into 3 initiating pathways: the classical, lectin, and alternative pathways. Proper functioning of each pathway is required for coordinated activity of innate and acquired immunity. The 3 initiating pathways all converge at C3 to generate an enzyme complex known as C3 convertase, which cleaves C3 into C3a and C3b (Fig 1). The association of C3b with From Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, NY. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Andrew S. Bomback, MD, MPH, 622 West 168th Street, PH 4-124, New York, NY 10032. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2013.12.001

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C3 convertase results in generation of C5 convertase, which cleaves C5 into C5a and C5b. This cleavage triggers the terminal complement cascade, which comprises C5b, C6, C7, C8, C9, and regulators of these terminal complement proteins, such as clusterin and vitronectin. The terminal complement cascade culminates in the assembly of the membrane attack complex (MAC; also known as C5b-9) and subsequent cell lysis. Although all 3 pathways converge at a similar level and therefore have similar downstream targets, the pathways are distinct in their points of origin. Furthermore, the alternative pathway is constitutively active (described below); therefore, enhanced activity of this system is generally due to a loss of regulation. In contrast, the classical and lectin pathways are not constitutively active and need a ‘‘trigger’’ to stimulate activity. Until recently, the traditional view of complement’s role in glomerulonephritis was focused on the classical complement pathway. Specifically, the glomerular diseases typified as ‘‘hypocomplementemic’’ glomerulonephritides, such as lupus nephritis, acute postinfectious glomerulonephritis, and cryoglobulinemic MPGN, are marked by immune complex deposition on immunofluorescence (IF) microscopy, which, in turn, signals the triggering of the classical complement pathway by antigen-antibody interactions. Indeed, the presence of immunoglobulin (Ig; IgG, IgM, and/or IgA) and complement (C1q and/or C3) on IF microscopy staining of immune-complexmediated lesions infers that the classical pathway has been activated by an inciting cause or event that generally falls into 1 of 3 major categories: infectious (eg, acute postinfectious glomerulonephritis), autoimmune (eg, lupus nephritis), or malignancy associated (eg, proliferative glomerulonephritis in the setting of monoclonal gammopathy).1 Therefore, treatment of these lesions was appropriately focused on the trigger for the classical pathway, exemplified by the use of high-dose and relatively nonspecific immunosuppression in lupus nephritis. The last decade has seen a new focus on hypocomplementemic glomerular diseases because of the increasing

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awareness of proliferative glomerulonephritides that the histology of MPGN type II, only 25% of patients had stain for complement (usually C3) without Ig. This IF an MPGN pattern despite classic ultrastructural changes pattern denotes an antibody-independent means of comof electron densities along the glomerular basement plement deposition and points to dysregulation of the membrane.16 Subsequently, the designation MPGN alternative complement pathway. The alternative comtype II was discarded in favor of the more accurate plement pathway is constitutively active at a low level. and inclusive term of DDD. In addition, pathologists The term ‘‘tickover’’ has been used to describe this basal, began emphasizing in their reports the presence of isophysiologic activation of the alternative pathway by lated deposits of C3 in examples of MPGN type I and spontaneous hydrolysis of C3 and the production of type III (similar to the C3-only staining pattern of C3b, which binds factor B to yield a fluid-phase C3 conDDD), setting these cases apart from the more common vertase (C3bBb).2-4 However, this alternative pathway variants of type I and type III MPGN, which contained Ig. These Ig-negative lesions, initially called idiopathic C3 convertase is under tight modulation by soluble or MPGN with isolated C3 deposits, were also found to membrane-bound regulating proteins, including complehave other histologic patterns by LM and acquired the ment factor H, complement factor I, and membrane name C3 glomerulonephritis (C3GN).17 The term C3 cofactor protein (Fig 2). Thus, a genetic or acquired (ie, via autoantibodies or monoclonal gammopathies) defect glomerulopathy, which encompasses DDD and C3GN, in either the activation or modulation of the C3 converhas been proposed as an umbrella classification for tase could lead to a transformation from low-grade physany glomerulonephritis with isolated C3 staining that, iologic activity (tickover) to in turn, signals dysregulaunrestrained hyperactivity tion of the alternative comCLINICAL SUMMARY (diseases of complement plement pathway.18 3-10 dysregulation). In these Just how far this umbrella
A classification scheme that divides proliferative instances, therapies aimed extends is a fascinating and glomerulonephritides into immune-complex-mediated at specific components of growing area of research. In versus complement-mediated disease can facilitate an unthe alternative complement addition to the C3 glomeruderstanding of which components of the complement cascade are involved in the pathogenesis of kidney injury. pathway may prove to be lopathies and aHUS, diseffective, targeted therapies. eases that are felt to be
Eculizumab, a monoclonal antibody to C5, should be MPGN best exemplifies primarily mediated by geconsidered for all patients with atypical hemolytic uremic syndrome because dysregulation at the level of C5 is the importance of reclasnetic and/or acquired abnorgenerally homogenous in this disease. sifying lesions as immunemalities in the alternative complex-mediated vs complement pathway, more
The C3 glomerulopathies demonstrate variable degrees of C5 convertase dysregulation; therefore, they may not complement-mediated.11,12 common glomerular disuniversally respond to anti-C5 therapy. eases, such as IgA nephropaThe MPGN lesion has thy and diabetic kidney, have traditionally been cate
Blockade at the level of C3 may be an alternative to eculizumab therapy, primarily in patients with C3 been associated with dysregorized according to ultraglomerulopathies associated with greater C3 convertase gulation in the complement structural findings on dysregulation than C5 convertase dysregulation. cascade.19 Anti-neutrophil electron microscopy (EM). Subendothelial and mesancytoplasmic autoantibody gial deposits predominate (ANCA)-associated glomerin MPGN type I13; highly electrondense intramembraulonephritis has also recently emerged as a possible complement-mediated lesion. Although the hallmark nous and mesangial deposits are the hallmark of type II finding on IF staining in ANCA-associated glomerulone(also known as dense deposit disease [DDD])14; and in phritis is a paucity of Ig and complement deposition, most type III MPGN deposits can be subendothelial and cases have some focal complement deposition at sites of subepithelial (Burkholder subtype) or produce complex glomerular injury.20 In ANCA-mediated disease, ANCA intramembranous, subendothelial, and subepithelial formations with fraying of the lamina densa (Strife and AnIgG activates cytokine-primed neutrophils that, in turn, ders subtype).15 However, this classification scheme was release factors that stimulate activity of the alternative complement pathway. In mice, administration of antinot without its problems; for example, within the same myeloperoxidase (MPO) IgG leads to a necrotizing, biopsy or the same glomerulus, pathologists may observe crescentic glomerulonephritis with neutrophil and macrooverlapping features among these subtypes. phage infiltration alongside low-level glomerular IgG and The major drawback to the EM-based classification C3 deposition. In contrast, co-administration of anti-MPO scheme was that it was based on histopathology patIgG with cobra venom factor, which depletes C3, protects terns and not pathophysiology of disease. For example, against the development of such a lesion.21 A similar ‘‘resismany patients with intramembranous dense deposits, characteristic of MPGN type II, lacked an MPGN pattern tance’’ against anti-MPO-mediated glomerulonephritis was altogether on light microscopy (LM). In a large study of shown in knockout mice deficient in C5 and factor B (both

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Figure 1. Classical vs alternative complement pathways. The complement system is divided into 3 initiating pathways (classical, lectin, and alternative pathways) that all converge at the level of C3 to generate a C3 convertase that cleaves C3 into C3a and C3b. The association of C3b with C3 convertase results in generation of C5 convertase, which cleaves C5 into C5a and C5b. The C3 convertase and C5 convertase of the classical pathway is distinct from the convertase complexes of the alternative pathway. The terminal complement cascade, which comprises C5b, C6, C7, C8, C9, and regulators of these terminal complement proteins, culminates in the assembly of the MAC (also known as C5b-9) and subsequent cell lysis. The classical pathway is not constitutively active and needs a ‘‘trigger’’ in the form of antigen-antibody interaction to stimulate activity. In contrast, the alternative pathway is constitutively active by the ‘‘tickover’’ phenomenon; therefore, enhanced activity of this system is generally due to a loss of regulation that can occur via mutations,4,8,9 autoantibodies,3-5,10 or monoclonal gammopathies.6,7 Abbreviation: MAC, membrane attack complex.

proteins of the alternative pathway) but not in mice deficient in C4 (an important protein of the classical and lectin pathways).21

Anti-Complement Therapy: Targeting C5 The first available anti-complement therapy is eculizumab, a fully humanized monoclonal antibody that binds with high affinity to C5 and prevents the generation of MAC. Eculizumab was engineered to target C5 while minimizing its own potential to elicit an inflammatory response. The C5-specific variable regions were fused to a kappa light chain and a hybrid heavy chain created from portions of IgG2 and IgG4. IgG2 constant region 1 and hinge region were chosen because they do not bind Fc receptors or activate complement. IgG4 constant regions 2 and 3 were selected for their inability to activate complement.22 Dosed intravenously, eculizumab has a half-life of approximately 11 6 3 days (hence the conventional maintenance dosing of every other week once the drug has been loaded) and achieves complete complement blockade when its serum concentration reaches 35 mg/mL.22 Eculizumab was first approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH)23 and, more recently, for treatment of aHUS on the basis of treatment data from 27 patients treated in off-label studies and 37 patients in 2 phase II trials.24 The second of these phase II trials, with 20 participants, was notable for 80% of subjects achieving thrombotic microangiopathy eventfree status, defined as no decrease in the platelet count of greater than 25%, no plasma exchange or infusion, and no initiation of dialysis. In the first trial, 4 of 5 patients were able to discontinue hemodialysis. Overall, earlier inter-

vention with eculizumab was associated with significantly greater improvements in kidney function.25 Although eculizumab has revolutionized the treatment of aHUS, several unresolved issues remain. Two key questions—whether eculizumab should be the first-line therapy for aHUS and whether the drug must be considered lifelong therapy—are closely interrelated and influenced heavily by the exceedingly high cost of treatment. Prior experience with eculizumab in treating PNH has involved prolonged, often lifelong, courses of therapy because of the relapsing nature of the disease, a similar phenomenon seen with aHUS.26,27 Because some aHUS patients have responded to limited courses of plasmapheresis, it may be beneficial and economically advantageous to start patients on plasmapheresis and only use eculizumab for those patients who manifest resistance to or dependence on plasmapheresis. However, some authors have advocated that this policy should only be used in adult patients and that children with aHUS should receive eculizumab as first-line therapy to avoid complications associated with plasmapheresis and central venous catheters.24 The role of eculizumab in prevention of posttransplant aHUS recurrence is another important area of research. The rate of recurrent aHUS in the allograft has been reported to be 50%, but most believe this incidence is artificially low (perhaps influenced by premature loss of the allograft to other reasons) and that specific variants of aHUS will inevitably recur over the lifetime of a functional graft. Before the advent of eculizumab therapy, combined liver-kidney transplantation for aHUS was considered the most viable route to avoid such recurrence. Eculizumab clearly obviates this potentially morbid operation, but again the issue of cost of therapy arises: Should

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Figure 2. Regulation of the alternative complement pathway. The alternative pathway is constitutively active because of the ‘‘tickover’’ phenomenon of spontaneous hydrolysis of C3 to C3b. This basal, physiologic activity is tightly regulated by activating proteins of the alternative pathway (eg, C3, factor B, factor D, all in green) and inhibitory or regulatory proteins of the alternative pathway (eg, factor H, factor I, membrane cofactor protein, all in red). A gain-offunction mutation in an activating protein or a loss of function mutation in a regulatory protein can lead to hyperactivity of the pathway; likewise, an autoantibody directed at either an activating or inhibitory protein could shift the alternative pathway from low-grade physiologic activity to pathophysiologic hyperactivity. Abbreviation: MAC, membrane attack complex.

eculizumab be used immediately after recognition of recurrence or, potentially, as prophylactic therapy initiated in the peritransplantation period?28 The ‘‘game-changing’’ results of eculizumab in PNH and aHUS have raised expectations that the drug may prove equally beneficial in the C3 glomerulopathies, which share many of the same abnormalities in alternative pathway regulation as aHUS and PNH. The literature to date on using eculizumab for C3 glomerulopathies is limited to 6 case reports29-34 and the results from a 1-year, open-label study of eculizumab therapy in 6 subjects.35,36 All but 1 of the 6 case reports document beneficial effects of eculizumab in treating patients with C3 glomerulopathies with improvements in serum creatinine, serum albumin, and/ or proteinuria (Table 1).29-34 It is important to note that the 1 case report that did not show clinical improvement when treating recurrent C3GN in the allograft with eculizumab was supported by protocol biopsies at 6 and 12 months of treatment that demonstrated progression of disease at the histopathologic level.34 An open-label study of eculizumab therapy in 6 subjects with C3 glomerulopathies (3 with DDD, 3 with C3GN, 3 with disease recurrent in allograft kidney) was

published in 2 parts: 1 focusing on clinical response to therapy35 and 1 focusing on the results of biopsies done pre- and post-treatment.36 All subjects were treated with eculizumab for 1 year with the same dosing schedule used for aHUS. Subjects had proteinuria greater than 1 g/day and/or acute kidney injury (serum creatinine $150% baseline) at enrollment. After 1 year of therapy, 2 subjects demonstrated significantly reduced serum creatinine with decreased mesangial and/or endocapillary proliferation on LM, 1 subject attained remission of nephrotic syndrome with reduced mesangial proliferation on LM and partial resorption of deposits on EM, and 1 subject had stable laboratory parameters but significantly reduced mesangial and endocapillary proliferation on LM. However, the 2 remaining patients demonstrated steeply declining kidney function during treatment. Taken together, the results from the case reports and open-label study indicate that eculizumab may be an appropriate treatment for a subgroup of patients with DDD and C3GN, but it clearly does not fit all patients with C3 glomerulopathies and may carry the potential for worsening of disease in some patients. This variation in response to C5 blockade highlights the differences

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Table 1. Case Reports of Eculizumab Therapy in C3 Glomerulopathies Reference

N 32

Disease

Native/Transplant

C3Nef

Response Y SCr Y Proteinuria Y SCr Y Proteinuria [ SAlb Y Proteinuria [ SAlb Y SCr Y Proteinuria [ SAlb Progression of disease* Y Proteinuria

McCaughan et al, 2012

1

DDD

Transplant

(1)

Daina et al, 201231

1

DDD

Native

(1)

Vivarelli et al, 201230

1

DDD

Native

(1)

Radhakrishnan et al, 201229

1

MPGN type 1

Native

(1)

Gurkan et al, 201334 Kerns et al, 201333

1 1

C3GN C3GN

Transplant Native

(1) Not reported

Abbreviations: C3GN, C3 glomerulonephritis; C3Nef, C3 nephritic factor; DDD, dense deposit disease; MPGN, membranoproliferative glomerulonephritis; SAlb, serum albumin; SCr, serum creatinine. *Creatinine and proteinuria levels were unchanged during 1 y of therapy whereas repeat allograft biopsies at 6 and 12 mo showed continuously active glomerulonephritis with increased chronicity.

between C3 glomerulopathies and aHUS. Some investigators have suggested that aHUS should be considered part of a spectrum that includes DDD and C3GN given the overlap in genetic abnormalities (eg, mutations in factor H, factor I, membrane cofactor protein, C3, and factor B) and autoantibodies (eg, anti-factor H autoantibodies) reported in these diseases.5,37-39 However, despite sharing common genetic and autoimmune risk factors with DDD and C3GN, aHUS should not be considered a C3 glomerulopathy. The distinction can be made solely on histopathology. Whereas in aHUS glomerular damage is due to the thrombotic microangiopathy (TMA), injury in the C3 glomerulopathies is from deposition of complement debris in the glomerular basement membrane.40 Furthermore, there is typically no associated C3 staining on IF or electron-dense deposits on EM in cases of aHUS. However, the distinction between aHUS and the C3 glomerulopathies may be most important, particularly in considering anti-complement therapy, on a pathophysiologic level. Specifically, aHUS differs from the C3 glomerulopathies in where the alternative pathway dysregulation occurs. The alternative pathway consists of a network of complement proteins in either the fluid phase as soluble plasma proteins or in the solid phase as cell membrane proteins. The underlying defect in most instances of the C3 glomerulopathies (and in all cases of DDD) is felt to be excessive activation of the alternative complement pathway in the fluid phase.11,41,42 In contrast, the endothelial damage that is the hallmark of aHUS is due to dysregulation at the level of the cell membrane or in the solid phase.2 This solid-phase dysregulation makes aHUS a more homogenous disease than the C3 glomerulopathies in terms of prognosis and response to anti-C5 therapy. The solid-phase dysregulation in aHUS translates to C5 convertase dysregulation being at least equal and often greater than C3 convertase dysregulation. Hence, blockade of C5 in this disease is expected to yield

improvement. In contrast, the heterogeneity of fluidphase dysregulation in C3 glomerulopathies in some cases is associated with C3 convertase dysregulation being greater than C5 convertase dysregulation and in other cases with C5 convertase dysregulation being greater than C3 convertase dysregulation.43 Only the latter cases would be expected to respond to eculizumab, and the former cases, because of a feedback effect on C3 convertase activity, could potentially be aggravated by C5 blockade. Therefore, one of the major challenges in treating patients with C3 glomerulopathies with anti-complement therapy is how to distinguish the patient with primarily C3 convertase dysregulation from the patient with primarily C5 convertase dysregulation. Speculatively, the mass spectrometry techniques reported by Sethi and colleagues, which have shown components of the alternative and terminal complement pathway in glomeruli of patients with C3 glomerulopathies that were not seen in glomeruli of normal controls nor, to the same extent, in glomeruli of patients with immune complex-mediated MPGN,40 hold the potential to distinguish deposits primarily composed of breakdown products from C3 convertase hyperactivity vs C5 convertase hyperactivity. Levels of soluble membrane attack complex (sMAC), which can be measured from whole blood samples, may also be informative because elevated levels in a patient with C3 glomerulopathy likely implicate a high degree of C5 convertase dysregulation.43 Indeed, in the open-label study of eculizumab for DDD and C3GN, the sMAC levels of the responders normalized immediately on therapy and paralleled improvements in serum creatinine and proteinuria whereas the nonresponders had normal levels of sMAC before therapy.35 These observations hold forth the promise that elevated sMAC before eculizumab treatment may be a predictor of response. Conversely, normal sMAC levels may be a contraindication to using this therapy.

Anti-complement Therapy for GN

Interest in blockade of C5 has recently arisen in the treatment of ANCA-associated glomerulonephritis. As discussed earlier, mice deficient in C5 (via knockout technique) have demonstrated resistance against anti-MPO-mediated glomerulonephritis.21 Likewise, in subsequent studies, pretreatment with an anti-C5 monoclonal antibody has been shown to prevent development of necrotizing and crescentic glomerulonephritis induced by anti-MPO IgG in mice, and, in a more clinically relevant scenario, intervention with anti-C5 therapy 7 days after administration of the anti-MPO IgG significantly reduces the degree of crescent formation and fibrinoid necrosis.44 Given the high morbidity and mortality seen in ANCA-associated glomerulonephritis despite conventional therapy, investigators have sought to explore whether adding anti-C5 therapy can improve overall outcomes in this disease. An open-label phase II trial (NCT01275287), in which patients with ANCAassociated glomerulonephritis and/or small-vessel vasculitis were randomized to standard-of-care treatment (cyclophosphamide and steroids) vs standard of care plus eculizumab, was withdrawn because of lack of enrollment. However, more recently, another phase II trial (NCT01363388) in ANCA-associated glomerulonephritis, using the C5aR blocker CCX168, has begun with a planned enrollment of 60 subjects randomized to either placebo or CCX168 for 84 days on top of standard cyclophosphamide induction therapy.

Anti-Complement Therapy: Targeting C3 In theory, blockade at the level of C3 may be more effective than anti-C5 therapy for the C3 glomerulopathies given that all of the identified complement abnormalities in these diseases converge at the level of abnormal C3 convertase activity. In contrast, concomitant dysregulation of the C5 convertase is more variable. Recently, Zhang and colleagues reported results using soluble CR1 (sCR1) in mice deficient in factor H (a model for C3GN) and transgenic for human CR1.45 CR1 is a cell-surface protein expressed on several cells, including B cells, some T cells, dendritic cells, and podocytes, with regulatory activity at the level of C3 convertase and C5 convertase. In addition, CR1 is the only cofactor of factor I that can cleave inactive C3b into smaller fragments, potentially clearing this breakdown product of the C3 convertase away from the glomerular basement membrane. Daily intraperitoneal injections of sCR1 in factor H-deficient mice led to increases in serum C3 levels and, histopathologically, decreases in C3 deposition with clearance of old C3 deposits demonstrated by reduced C3c staining. In this same report, Zhang and colleagues detail the short-term use (7 doses) of sCR1 in an 8-year-old girl with ESRD due to DDD. Serum C3 levels increased and sMAC levels normalized transiently, although no differences were seen in biopsies performed before and after treatment. It is

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important to note that no adverse effects were reported, including no development of anti-sCR1 antibodies.45 This group is currently enrolling patients for a small phase I trial (n ¼ 5) of sCR1 (also called CDX-1135) in pediatric and adult patients with DDD (NCT01791686). Treatments aimed at the level of C3 may be particularly needed for patients with DDD given the high prevalence of C3 nephritic factors (C3Nefs) seen in that population. This autoantibody directly stabilizes the C3 activating complex of the alternative pathway and prevents the inhibitory actions of factor H.46-48 By blocking the normal actions of factor H and other regulators of complement activation, C3Nefs prolong the half-life of C3 convertase from a few seconds to up to 60 minutes.49 The massive C3 consumption that ensues leads to very low levels of serum C3 (a common finding in DDD and, to a lesser degree, in C3GN) and generation of more C3 convertase and C5 convertase. C3Nefs are detected in the serum of approximately 80% of patients with DDD and 40% to 50% of patients with C3GN, and they may explain, at least in part, the worse long-term prognosis associated with DDD compared with C3GN.12

Conclusion The improved understanding of the role of alternative complement dysregulation in the pathogenesis of a subgroup of glomerular diseases, to date, has not been fully matched by advances in treating these diseases. The advent of anti-complement therapies will hopefully address this gap. Eculizumab, which targets complement at the level of C5, has revolutionized the treatment of aHUS, but it likely will not be an equally game-changing drug for the more heterogeneous entities of C3GN and DDD. However, safe and effective blockade at the level of C3 could provide more definitive therapy for these C3 glomerulopathies.

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