Kidney Disease Caused by Dysregulation of the Complement Alternative Pathway: an Etiologic Approach

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Kidney Disease Caused by Dysregulation of the Complement Alternative Pathway: An Etiologic Approach

† ‡ ‡ An S. De Vriese,* Sanjeev Sethi, Jens Van Praet,* Karl A. Nath, and Fernando C. Fervenza

*Division of Nephrology, AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium; and Divisions of †Anatomic Pathology and ‡Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota

ABSTRACT Kidney diseases caused by genetic or acquired dysregulation of the complement and atypical postinfectious GN. aHUS is a alternative pathway (AP) are traditionally classified on the basis of clinical presentation thrombotic microangiopathy (TMA) typ- (atypical hemolytic uremic syndrome as thrombotic microangiopathy), biopsy appear- ified by the triad of AKI, microangiopathic ance (dense deposit disease and C3 GN), or clinical course (atypical postinfectious GN). hemolytic anemia, and thrombocytope- Each is characterized by an inappropriate activation of the AP, eventuating in renal nia, and clinically, it is often indistinguish- damage. The clinical diversity of these disorders highlights important differences able from thrombotic thrombocytopenic in the triggers, the sites and intensity of involvement, and the outcome of the AP purpura. The C3 glomerulopathies are dysregulation. Nevertheless, we contend that these diseases should be grouped as characterized by C3 accumulation, with disorders of the AP and classified on an etiologic basis. In this review, we define absent or scanty glomerular Ig deposition different pathophysiologic categories of AP dysfunction. The precise identification of on immunofluorescence examination.3 the underlying abnormality is the key to predict the response to immune suppression, This recently coined group includes both plasma infusion, and complement-inhibitory drugs and the outcome after transplan- C3 GN and dense deposit disease (DDD), tation. In a patient with presumed dysregulation of the AP, the collaboration of the which are discriminated from each other clinician, the renal pathologist, and the biochemical and genetic laboratory is very much by the location and appearance of the glo- encouraged, because this enables the elucidation of both the underlying pathogenesis merular deposits on electron micros- and the optimal therapeutic approach. copy.4,5 Atypical postinfectious GN refers to a clinical course where the diagnosis of J Am Soc Nephrol 26: 2917–2929, 2015. doi: 10.1681/ASN.2015020184 postinfectious GN is not followed by res- olution but by signs of persisting glomerular damage.6 Inappropriate activation or The complement system contributes in- complement cascade is initiated by the C5 modulation of the C3 convertase is the dispensably to immunologic homeostasis convertase and ultimately, generates the pathophysiologic process common to all in at least three major ways. First, this membrane attack complex inducing cell of these diseases and the one that instigates system is an essential part of innate im- lysis. The C3 convertase amplification tissue injury. munity that serves as the first-line defense loop requires rigorous control to prevent C3 glomerulopathies are typically char- against infections and nonmicrobial forms inadvertent tissue inflammation and dam- acterized by uncontrolled activation of the of stress. Second, it provides an interface age (Figure 2). Certain regulatory proteins AP in the fluid phase (i.e., in the circula- betweentheinnateandadaptiveimmunity, reside on the cell surface and provide cy- tion) and/or at tissue surfaces that and third, it contributes to immune sur- toprotection, whereas others exist in lack membrane–anchored complement veillance by clearing foreign or apoptotic plasma and limit fluid–phase complement cells.1,2 activation. The key stepinthe complement cascade Published online ahead of print. Publication date available at www.jasn.org. isthecleavageofC3toC3aandC3b affected by C3 convertase activity; the latter PATHOGENESIS Correspondence: Prof.AnS.DeVriese,Divisionof Nephrology and Infectious Diseases, AZ Sint-Jan may originate from the classic, lectin, or Brugge, Ruddershove, 10, B-8000 Brugge, Belgium. alternative pathways (APs) (Figure 1). The Kidney diseases caused by dysfunction of Email: [email protected]

C3 convertases continuously cleave C3 in a theAPcompriseatypicalhemolyticuremic Copyright © 2015 by the American Society of powerful ampliﬁcation loop. The terminal syndrome (aHUS), C3 glomerulopathies, Nephrology

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The predilection for the kidney of disorders of the AP is incompletely un- derstood but may be related to the presence of the fenestrae continuously exposing the acellular subendothelial tissues to complement activators, a lower baseline expression of complement regulators, and/or differences in the com- position of the glycocalix.10 Transitions between glomerulopathies included in this spectrum can occur during the disease course,11–14 after kidney transplantation,15,16 or among members of the same family,17 adding another layer of complexity to AP pathophysiology. The cause of this potential variation between phenotypes is pres- ently unknown. The overactivation of the AP may be either constitutive or triggered. The AP is constitutively active owing to the slow spontaneous tick over of C3, leading to the formation of the AP C3 convertase. Agenetic Figure 1. The normal complement cascade. The complement system can be activated by the or acquired defect in the regulators of classic pathway, the lectin pathway, and the AP, all resulting in the formation of C3 convertases. complement activation may lead to un- The classic pathway is initiated by immune complexes that interact with C1q, ultimately leading totheformationoftheclassic pathwayC3convertaseC4bC2a.Thelectinpathway generatesthe checked spontaneous activation of the AP. same C3 convertase C4bC2a but is activated by the binding of mannose-binding lectins (MBLs) In some instances, the defect is not severe to carbohydrate moieties found primarily on the surface of microbial pathogens. The AP is enough to cause dysregulation in baseline capable of autoactivation by a mechanism called tick over of C3. Tick over occurs spontaneously circumstances, but a trigger may lead to 6 at a low rate, generating a conformationally changed C3, which is referred to as C3(H2O). overactivation of the complement pathway. C3(H2O) is capable of binding CFB, resulting in the cleavage of CFB by complement factor In these patients, sustained complement ac- D (CFD) and generating Ba and Bb and the formation of the AP C3 convertase C3 (H2O)Bb.Any tivation occurs in what otherwise would of the C3 convertases can cleave C3 to C3a and C3b. The C3b fragment can bind to CFB. After have been a self-limiting event. The eliciting the cleavage of CFB by CFD, the C3 convertase C3bBb is formed. This C3 convertase cleaves condition is most often an infection, a well fi more C3 to C3b to generate even more C3 convertase in a powerful ampli cation loop, re- known trigger for aHUS. A similar mecha- sulting in the full activation of the complement system. The plasma protein properdin stabilizes nism likely is at play in the C3 glomerulo- C3bBb and provides a platform for its in situ assembly on microbial surfaces, apoptotic cells, and malignant cells. C3b also initiates the terminal complement cascade by the formation of the pathies. In patients originally diagnosed C5 convertase through association with either of the C3 convertases (C4bC2aC3b or with postinfectious GN, AP abnormalities C3bBbC3b). The C5 convertase then cleaves C5 to C5a and C5b. C5b subsequently binds to were detected, and subsequent biopsies C6, facilitating the binding of C7, C8, and C9 and culminating in the formation of the C5b-9 were consistent with C3 glomerulo- terminal membrane attack complex (MAC). The latter forms pores in the membrane of pathy.6,18,19 Other triggers include vaccina- pathogens and damaged self-cells, thus promoting cell lysis. C3a and C5a are anaphylatoxins tions, immunosuppressive or antineoplastic and among the most powerful effectors of complement activation capable of inducing che- drugs, oral contraceptives, pregnancy, and motaxis, cell activation, and inflammatory signaling. MASP, mannose-binding lectin–associated childbirth. The development of a monoclo- serine protease. nal gammopathy, possibly acting as an autoantibody, may also be a precipitating regulators.7 The glomerular basement response (Figure 3).4,8 aHUS, however, event. membrane (GBM) represents such a sen- generally results from AP dysregulation The expression of disease may also be sitive surface that it exclusively depends at the level of the cell membrane with determined by the site of the defect in the on attached soluble regulators, such as impaired cell surface protection against AP.The presence of several defects may be complement factor H (CFH), for protec- complement activation.9 The microvas- required to instigate clinical disease, which tion. As a consequence, continuous de- cular endothelium is targeted generally, was illustrated by the finding of genetic position of C3 and complement debris and the renal microvascular endothelium abnormalities in clinically unaffected rel- within the GBM occurs, with attendant is targeted particularly, thereby leading atives. Such combinations include more glomerular injury and a proliferative to a TMA4 (Figure 4). than one mutation,20 amutationand

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disease(Figure5);.160 mutations inCFH are currently identified (www.FH-HUS. org), resulting in deficiency or dysfunction of CFH (Figure 6A). Mutations that lead to complete absence of CFH (type I mutations)24–27 or a CFH that is expressed in plasma but lacks complement regulatory activities (type II mutations)28–30— generally located at the N terminus—result in uncontrolled complement activation in the fluid phase and GBM. The phenotypic expression is that of a proliferative GN.6,23,25,31–34 However, the majority of the aHUS-associated mutations cluster in the C-terminal recognition domain.9,20,26 The mutant CFH proteins generally show normal regulatory activity in the fluid phase but display defective recognition and regulatory functions at the surface of endothelial cells, eventuating in TMA. The majority is heterozygous missense mutations associated with normal CFH plasma levels. Mutations per se do not determine Figure 2. Normal regulation of the complement AP. CFI is responsible for the proteolytic disease phenotype (Table 1). Indeed, inactivation of C3b to iC3b (inactive C3b) and ultimately, the C3 breakdown products C3d there is an emerging consensus that and C3g, thus irreversibly preventing reassembly of the C3 convertase. MCP (CD46) is regards most of the identified CFH mu- a surface-expressed regulator that has decay accelerating activity and acts as a cofactor for tations as predisposing rather than caus- CFI. CFH is one of the most important regulators of the AP, controlling complement ac- ative and that additional insults, either tivation in several ways. It decreases the formation of C3b by competing with CFB in binding genetic or environmental, are required to C3b and accelerating the dissociation of the C3bBb convertase complex (decay ac- to initiate clinical disease. For example, celerating activity). In addition, it acts as a cofactor for CFI in the cleavage of C3b to iC3b in in a series of 795 patients with aHUS, concert with MCP. CFH protects against complement-mediated damage both in the fluid phase and on the host cell surface. Additional control of the cascade occurs through the concurrence of CFH with membrane co- CFHR protein family. CFHR consists of five proteins that are structurally and functionally factor protein (MCP) risk haplotypes related to CFH: CFHR1, CFHR2, CFHR3, CFHR4, and CFHR5. These CFHR proteins significantly increased the disease pene- compete with CFH for binding to C3b but have no direct complement inhibiting actions. trance.20 In another series of patients Although the CFH-C3b interaction prevents further C3b generation, the CFHR protein-C3b with aHUS, either mutations or dis- interaction enables C3b amplification to proceed unhindered. This process is termed CFH ease-associated polymorphisms in CFH deregulation. The ratio between CFH and CFHR proteins is, thus, critical for fine tuning were found in the large majority of complement regulation. pregnancy-associated aHUS and post- transplant aHUS,22 suggesting that these a permissive genetic background,21 and a sites in the AP where dysregulation may so–called secondary forms of aHUS are mutation with an autoantibody.22,23 occur. Within each mechanistic category, genetically determined and that preg- different clinical phenotypes may present. nancy and the immunosuppressive Unraveling the site of AP dysfunction is drugs serve as environmental triggers. SITES OF AP DYSREGULATION important, because it may assist in appropriate management. Functional Inactivation of CFH by an Historically, patients have been grouped Autoantibody into clinical syndromes (C3 glomerulopa- Deficiency or Dysfunction of CFH The presence of an autoantibody directed thiesversusTMAs)asalogicalapproach CFH is a single–polypeptide chain glyco- against CFH results in functional CFH from the point of view of the clinician. protein composed of 20 repetitive units deficiency and occurs in 6%–25% of However, recent data show that these of 60 amino acids each termed short con- Europeans35–38 and 56% of Indians diseases share a common pathophysiology sensus repeats. Insight into its structure- with aHUS.39 These antibodies bind andshouldbeconsideredasdisordersof function relationship contributes to the with the C-terminal region of CFH, where the AP. In this section, we define different understanding of CFH–associated renal also, the majority of aHUS–associated

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exhibit homozygous deficiency for CFHR1/CFHR3 but lack the anti-CFH autoantibodies do not develop aHUS. Com- plete deficiency of CFHR1 is most likely the significant factor associated with the generation of the anti-CFH autoantibodies, possibly because of the failure of immune tolerance to the homologous region in CFH.38 In a patient with DDD, a monoclonal light–chain dimer with CFH-inhibiting effects was discovered.41 The mini autoantibody was later shown to interfere with the regulatory domain of CFH, en- Figure 3. Representative kidney biopsy findings from a single patient with (A–C) DDD and tailing uncontrolled complement activa- fl 42 (D–F) C3 GN. (A) Light microscopy shows a membranoproliferative pattern of injury with tion in the uid phase. Anti-CFH thickened GBMs and mesangial and endocapillary proliferation. Periodic acid–Schiff stain. autoantibodies have been described in Original magnification, 340. (B) Immunofluorescence microscopy shows bright granular other patients with DDD,43,44 with a C3 staining in the mesangium and along capillary walls. Staining for all Igs and C1q was similar predilection for the N-terminal negative. Original magnification, 340. (C) Electron microscopy features dense deposits complement regulatory domain of along the GBMs (thick black arrow). Original magnification, 34400. (D) Light microscopy CFH.43 Interestingly, in a patient with – shows a predominantly mesangial proliferative GN. Periodic acid Schiff stain. Original anti-CFH autoantibodies, membrano- fi 3 fl magni cation, 40. (E) Immuno uorescence microscopy shows bright staining for C3 in proliferative glomerulopathy occurred the mesangium and along the capillary walls. Immunofluorescence studies for IgG, IgM, k l fi 3 in the native kidneys and recurred rap- C1q, and -and -light chains were negative. Original magni cation, 40. (F) Electron fi microscopy shows numerous mesangial (black arrows) and few capillary wall deposits idly after the rst kidney transplant but (white arrows). Original magnification, 32900. transitioned to aHUS in a second trans- plant16; such clinical observations indicate that the presence of the antibody itself does not predict phenotypic expression.

Mutations Affecting CFHR Proteins The CFH gene and the genes encoding the five CFHR proteins show large degrees of sequence identity favoring genomic rearrangements, including deletions, duplication, and generation of hybrid genes.45 Figure 4. Representative kidney biopsy findings in aHUS. (A) Fibrin thrombi in the glo- The CFHR proteins are highly related in fi merular capillary lumen (black arrow points to brin thrombi; silver methenamine stain). structure, and CFHR1, CFHR2, and Original magnification, 340. (B and C) Electron microscopy showing subendothelial ex- fl fi CFHR5 share a common dimerization pansion by uffy granular material (white arrows), cellular debris, and brin (black arrows). motif. The formation of homodimers and Also note the endothelial injury with swelling and loss of fenestration. Original magnifi- heterodimers promotes the binding to li- cation, 34800 in B; 313,000 in C. gands and permits the CFHR proteins to act as competitive antagonists of CFH, a CFH mutations cluster, thus affecting plement factor H–related (CFHR) proteins property termed CFH deregulation.46 the surface binding and recognition CFHR1 and CFHR3 and the absence of However, generation of mutant CFHR function of CFH.37,38 However, a subse- CFHR1 and CFHR3 in plasma.22,35,37–40 proteins by internal duplication or gene fu- quent extensive characterization of the This association has been labeled deficiency sion leads to unusual CFHR protein dimers autoantibodies in 19 patients with aHUS of CFHR proteins and CFH autoantibody- and multimers with enhanced avidity for showed that the antibodies bind multi- positive (DEAP)–hemolytic uremic syn- ligands, enabling the CFHR proteins to ple epitopes on CFH and perturb both drome (HUS; deficiency of CFHR proteins outcompete CFH and amplify the degree fluid–phase and cell surface comple- and CFH autoantibody–positive HUS).37 of CFH deregulation46 (Figure 6B). This ment control.40 CFHR1/CFHR3 deficiency is, however, a genetic scenario is recognized in families In most patients, the presence of the anti- common polymorphism found in 2%–8% with C3 glomerulopathy47–52 (Table 2). CFH autoantibodies is associated with a of the normal population.40 Family mem- Several hybrid genes deriving from homozygous deletion of the genes for com- bers of patients with DEAP-HUS who the CFH/CFHR region have also been

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GN) was reported in a patient with a heterozygous mutation in CFHR5 causing premature truncation58 (Table 2). How this mutation is associated with the disease is currently unknown.

Stabilization of the C3 Convertase Gain-of-Function Mutations in Com- plement Factor B Figure 5. Structure-function relationship of CFH. CFH consists of 20 short consensus re- In aHUS, different gain-of-function mu- peats (SCRs) with two main functional domains positioned at the opposite ends of the tations in complement factor B (CFB) are protein. The N terminus (SCRs 1–4) is responsible for the fluid–phase complement regu- recognized.59–62 The mutant proteins latory functions (more specifically, the cofactor and decay-accelerating activity). The form a hyperfunctioning C3 convertase C terminus (SCRs 19 and 20) mediates the recognition of ligands and binding to cell sur- that is resistant to decay by CFH, thereby faces and tissue matrices, thus distinguishing self from nonself. The CFH mutations in aHUS activating the AP on the cell surface and mainly affect the surface recognition sites in SCRs 19 and 20. in the fluid phase. CFB mutations, however, are not uniformly pathogenic.61

Gain-of-Function Mutations in C3 Gain-of-function mutations in C3 occur in aHUS. These mutations impair regulation by MCP and confer resistance to cleavage by complement factor I (CFI) with21 or without63,64 increased afﬁnity for CFB. Dysfunctional C3 molecules resistant to inhibition by CFH also occur in C3 glomerulopathies.65–67 Such mutant C3 convertases resist inactivation by CFH but are regulated normally by decay-accelarating factor and MCP.These characteristics cause a ﬂuid phase– restricted AP dysregulation and a normal regulation on the cell surface, explaining the DDD phenotype.67 In a family with mutations in both C3 and MCP, some family members present with aHUS, whereas others exhibit C3 GN.17

C3 Nephritic Factor C3 nephritic factors (C3Nefs) comprise IgG and IgM autoantibodies that bind Figure 6. Sites of complement pathway dysregulation. (A) Loss of CFH inhibition. De- directly to the C3 convertase or its ficiency or dysfunction of CFH results in excessive generation of C3b, because the AP C3 components, thereby rendering it resis- convertase continuously produces C3b that is not degraded. (B) CFH deregulation. Ab- tant to spontaneous or CFH- and CFI- normal CFHR proteins with higher affinity outcompete CFH, resulting in less inhibition of the mediated decay. The prolonged survival C3 convertase and excessive generation of C3b. (C) Stabilization of the C3 convertase. of the C3 convertase massively consumes Hyperfunctional C3 results in excessive generation of C3b, despite normal function of the C3 and markedly reduces C3 levels. regulatory mechanisms. (D) Impaired inactivation of C3b to iC3b. Deficiency or dysfunction C3Nefs exist in .80% of patients with of CFI or MCP impairs degradation of C3b, resulting in increased levels of C3b. DDD and 40%–50% of patients with C3 GN.23,68,69 C3Nefs may also occur in acute poststreptococcal GN70,71 and identified in familial and sporadic aHUS, antagonist of CFH but lacks CFH regula- atypical postinfectious GN.6 including hybrid CFH/CFHR153–56 and tory activity at the cell surface. The specificcontribution of C3Nefs to CFH/CFHR3 genes57 (Table 2). The resul- A case of persistent GN after a strepto- the pathophysiology of AP disorders tant hybrid protein acts as a competitive coccal infection (atypical postinfectious remains undefined. C3Nefs occur in

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Table 1. Examples of variable phenotypic expression of CFH mutations functional significance occurs in C3 23 Mutation in CFH Phenotypical Expression Reference GN, Hemolysis Elevated Liver enzymes Prol621Thr Patient with C3 glomerulopathy later 12 and Low Platelets syndrome, and Shiga – 84 develops aHUS toxin associated HUS. Tyr899Stop Patient with aHUS develops C3 15 Clinical disease associated with MCP glomerulopathy in transplant kidney mutations exhibits highly variable pen- Ala161Ser; Arg1210Val; Arg53Cys Identified in patients with aHUS 23 etrance and commonly requires some and C3 glomerulopathy type of endothelial stress. Suboptimal Asn1117Ser Crescentic and necrotizing GN in the 34 MCPactivity mayadequatelydefendhost region where aHUS mutations cluster cells from inappropriate complement activation in unstressed states but fails healthy individuals72 and asymptomatic these mutations. Mutations in CFI also to provide protection in the presence of family members of patients with DDD.29 occur in patients with immune com- an endothelial insult (such as infection, Furthermore, C3Nef levels do not seem plex GN.31,82 In some patients, the pres- drugs, or pregnancy). Alternatively, the to correlate with the course of the GN.23 ence of positive antinuclear antibodies, concomitant presence of other muta- Treatment directed at the autoantibody, in- antidouble-stranded DNA, or rheuma- tions or disease-promoting polymor- cluding high-dose steroids and rituximab, toid factor83 suggests the presence of an phisms may be required for full-blown does not consistently reduce C3Nef ac- underlying autoimmune process, and the manifestation of the disease. For exam- tivity and/or induce clinical remis- latter may synergize with CFI mutations, ple, a homozygous mutation with total sion.73–76 Finally, the presence of C3Nef thereby generating C3b from C3. Inter- lack of MCP expression is described in often coincides with mutations in AP estingly, CFI mutations have not been not only a patient with aHUS but also, a proteins—most often CFH23,28,29 and reported in DDD. Although CFH completely healthy sibling (Figure 6D).85 less commonly, CFI and MCP.23 Genetic knockout mice acquire subendothelial abnormalities may, thus, promote auto- C3 deposits, combined CFH and CFI Monoclonal Gammopathy – immune phenomena directed against knockout mice do not develop C3 glo- In adult patients with C3 GN86 89 and – neo epitopes exposed on activated comple- merulopathy.82 Taken together, these DDD,90 92 compared with the general ment components. results indicate that CFI and the C3 population, the prevalence of monoclo- degradation products generated by nal gammopathy is greatly increased. Other Autoantibodies CFI are essential for the pathogenesis Importantly, glomerular deposits con- Some patients with DDD lack C3Nefsbut of DDD. tain C3 and complement debris but not have autoantibodies against CFB44,77 or monoclonal proteins, thereby indicating C3b and CFB,78 with a similar stabilizing Mutations in MCP that the disease is not caused by direct effect on the C3 convertase (Figure 6C). Loss of function of MCP leads to de- deposition of the monoclonal Ig. Addi- creased protection of host cells—in tionally, evidence of AP activation is Impaired Inactivation of C3b to iC3b particular, glomerular endothelial cells— present in such patients. Although in Mutations in CFI from complement lysis without signifi- some patients, a permissive genetic Heterozygous mutations in the CFI gene cantly affecting complement control in background was reported,86,88,89,92 mu- leading to reduced CFI levels79,80 or the fluid phase. tations in CFH, CFI, and MCP were not functional deficiency of CFI81 incur an Mutations in MCP resulting in either identified. Overall, available evidence increased risk for aHUS. CFI mutations decreased expression or impaired cofac- would suggest that the monoclonal Ig previously identified in aHUS were later tor function are found in 7%–13% of may promote complement activation reported in C3 GN,23 thereby underscoring patients with aHUS20,22,81 and generally by acting as an autoantibody against the fact that the clinical phenotype is not associated with a favorable prognosis. CFH or another AP component. The simply determined by the presence of Another MCP mutation of uncertain plausibility of this scenario was elegantly

Table 2. Overview of mutations in CFHR protein genes Genetic Defect Phenotypical Expression Systemic C3 Levels References Duplication in the CFHR5 gene C3 glomerulopathy (CFHR5 nephropathy) Normal 47, 49, 51 Duplication in the CFHR1 gene C3 glomerulopathy Mildly decreased 52 Hybrid CFHR3/CFHR1 gene C3 glomerulopathy Normal 50 Hybrid CFHR2/CFHR5 gene C3 glomerulopathy Decreased 48 Hybrid CFH/CFHR1 gene aHUS Mildly decreased or normal 53–56 Hybrid CFH/CFHR3 gene aHUS Normal 57 Mutation in the CFHR5 gene Atypical postinfectious GN Decreased 58

2922 Journal of the American Society of Nephrology J Am Soc Nephrol 26: 2917–2929, 2015 www.jasn.org BRIEF REVIEW shown in a patient with DDD, which was those with MCP mutations was equally autoantibodies and/or mutant proteins discussed above.41,42 beneficial regardless of whether they that may compete with the functional were treated with plasma.81,95 proteins, and (3) it enables the adminis- In patients with gain-of-function mu- tration of higher volumes of plasma. TREATMENT tations in complement activation proteins, Before the availability of eculizumab, plasma infusion may also be ineffective or plasma therapy was the therapeutic main- A standard therapeutic regimen that fits a even counterproductive, because it pro- stay in aHUS, although controlled trials particular clinical phenotype does not vides additional complement substrate for showing its effectiveness are lacking. In exist. On the basis of current understand- the hyperfunctioning mutant protein. In a general, no difference in response ing, salient therapeutic strategies and their DDD pedigree with a novel mutation in the to plasma infusion versus plasma ex- underlying rationale are now outlined. C3 gene characterized by a mutant C3 change has been consistently ob- convertase resistant to CFH control, re- served.22,39,98 With the availability of Nonspecific Treatment placement therapies providing CFH are specific complement inhibitors, the The clinical presentation of the C3 futile.67 In DDD caused by a hybrid role of plasma therapy will likely be re- glomerulopathies is more heterogeneous CFHR2/CFHR5 protein that renders the stricted to bridging the period between than that of aHUS. Some patients with C3 convertase refractory to inhibition clinical presentation and initiation of C3 glomerulopathy are characterized and decay by CFH, plasma infusion targeted treatment. by a slow progression.69 In these pa- proved detrimental.48 Few reports address the efficacy of tients, nonspecific treatment measures, plasma exchange in C3 glomerulopathy. – such as BP control, proteinuria reduc- Liver Transplantation In three patients with DDD,99 101 aben- tion and lipid-lowering agents, can be Patients with mutations in the comple- eficial effect of plasma exchange was used on the basis of extrapolations ment regulatory proteins have avery high seen, but all patients also received ag- from data in other chronic glomerular risk for loss of the transplanted kidney gressive immunosuppression. In a pa- diseases. In C3 glomerulopathy cohorts, caused by thrombosis or recurrent dis- tient with DDD caused by a CFHR2/ the use of renin-angiotensin-aldosteron ease. Because CHF, CFI, CFB, and C3 are CFHR5 deregulating hybrid protein, system blockade was associated with predominantly synthesized by the liver, plasma exchange was initiated with the a better renal survival,23 and the simultaneous liver-kidney transplanta- intent of reducing the levels of the mu- combined use of renin-angiotensin- tion can correct the genetic abnormality. tant protein. Although the levels de- aldosteron system blockade and immu- To avoid perioperative hepatic failure creased substantially, the response was nosuppression was better than either caused by uncontrolled hepatic comple- short lived, and within 1–2 days, com- agent alone.90 mentactivation, patients are prepared for plement activation rebounded.48 surgery with intensive plasma therapy Replace Deficient Gene Products and recently, eculizumab as well.96,97 Al- Immunosuppression Plasma Infusion though short-term complications re- Direct effects of immunosuppression on Patients with type I mutations in com- main substantial, with mortality rates the AP components have not been shown. plement regulatory plasma proteins may up to 15%, the overall success rate (de- This approach rests heavily on the view benefit from replacement of the deficient fined as good function of both grafts and that acquired antibodies contribute to the factor. Because recombinant CFH is cure of the disease) with this approach pathophysiology of the disease and that currently not available, functionally in- is 80% in experienced centers.96 Con- the production of these antibodies can tact CFH can only be administered sidering the growing experience with be attenuated by immunosuppression. An through plasma therapy. The efficacy eculizumab and its success in preventing added potential benefit may be the sup- of this approach is attested to by success- disease recurrence post-transplant, in pression of anaphylatoxin–induced glo- ful outcomes with long–term intermit- each individual patient, the advantages merular inflammation. In DEAP-aHUS, tent plasma infusion in patients with C3 and disadvantages of combined liver- anti–CFH antibody titers correlate with glomerulopathy28,29 or aHUS93 caused kidney transplantation should be care- disease activity.35,36,39 Accordingly, the by complete CFH deficiency. In these fully weighed against those of kidney combination of immunosuppression patients, however, persistent disease transplantation followed by chronic (prednisone with or without cyclophos- control requires lifelong substitution eculizumab prophylaxis. phamide or rituximab) with plasma ex- therapy. change benefits clinical outcome35,39,102 In contrast, plasma therapy is inef- Eliminate Autoantibodies and/or along with the sustained reduction of the fective in patients with a single MCP Mutant Proteins anti–CFH antibody titers.102 Subsequent mutation, an outcome consistent with Plasma Exchange maintenance therapy with prednisone the fact that MCP is a membrane-bound The rationale for plasma exchange is and mycophenolate mofetil or azathio- and not a circulating protein.94 Indeed, 3-fold: (1) it replaces deficient or defec- prine reduces the risk of relapse by in patients with aHUS, the outcome of tive regulatory proteins, (2) it removes 91%.39

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In the absence of controlled trials, where activation of the terminal comple- So far, the effects of eculizumab have support for immunosuppression in C3 ment pathway is pathogenic. However, been described in only 14 patients with glomerulopathy relies on case reports and blockade of the complement cascade at C3 glomerulopathy, of which 9 patients case series that show variable efficacy, the level of C5 preserves the early comple- were diagnosed with DDD and 5 patients the latter being susceptible to inflation ment components, thereby leaving un- were diagnosed with C3 GN. Eight in- by publication bias. The uncertain/ checked the potential dysregulation of dividual patients were reported,73–75,109–113 unsatisfactory effects of immunosup- the C3 convertase. showing success in seven patients. These pression are clearly illustrated by the Eculizumab has revolutionized the optimistic results may be influenced by high recurrence rates of this disease in treatment of aHUS. Mainly given as publication bias and contrast with the allografts.103 In our opinion, a trial of im- rescue therapy because of resistance to more modest effects obtained in an mune suppression should be restricted to or complications with plasma therapy, open–label proof-of-concept study in those patients with increasing proteinuria, eculizumab caused complete remission six patients.68,114 In three of these six progressive loss of kidney function, or se- in 21 patients from a compilation of 24 patients, there was a clinical response vere inflammation on renal biopsy (e.g., patients from the literature (11 children to eculizumab: a decrease in either se- crescentic GN), and it should be interrup- and 13 adults).105 A query sent to all ne- rum creatinine or proteinuria.68 In ted in the absence of a rapid response. phrology centers in France retrospec- four of eight patients who underwent a tively identified 19 adults with aHUS repeat biopsy,68,111–114 eculizumab de- Treatment of Plasma Cell Dyscrasia that received eculizumab as first-line or creased mesangial proliferation, endoca- Although a causal relationship between a rescue therapy.106 The risk of reaching pillary proliferation, or inflammatory monoclonal gammopathy and dysregulation ESRD was reduced by one half compared cell infiltration. In the other patients, of the AP has yet to be rigorously shown, with recent historical controls.106 Fi- there was stable or progressive disease. therapy directed at the clonal disorder nally, in a prospective phase II trial in Interestingly, after treatment with eculi- should be considered in patients with an 37 patients (31 adults and 6 adolescents) zumab, all biopsies showed IgG-k stain- AP disorder, in whom a monoclonal with aHUS, eculizumab was associated ing of the glomeruli, tubular basement protein is detected. In patients with a with substantial renal recovery.107 The membrane, and vessel wall, consistent C3 glomerulopathy associated with a response to eculizumab was similar in with deposition of eculizumab itself.114 documented monoclonal gammopathy, patients with and without identified The long–term clinical effects of such chemotherapy resulted in improvement complement mutation or anti-CFH au- binding of eculizumab to renal tissue of renal function in some89 but not all86 toantibodies.107 Earlier intervention was are unclear. patients. associated with improved renal func- The phenotypic expression (DDD tion.106,107 Thesedatahaveledtothe or C3 GN) does not seem to predict Inhibit Complement Activation recommendation105–107 that eculizumab the response to treatment,68,73–75,109–113 The appropriate complement–inhibiting should be the first-line therapy when the although biomarker studies have strategy is determined by the underlying diagnosis of aHUS is unequivocal (i.e.,in suggested a greater terminal pathway ac- mechanism of complement dysregula- children, familial forms, relapses, and tivity in C3 GN compared with DDD.115 tion. Many complement inhibitors are recurrences posttransplantation), re- In contrast, elevated soluble membrane in clinical development,104 but so far, gardless of the results of the complement attack complex was found to be a marker only eculizumab has been approved for investigations. Screening of anti-CFH of response68 in accordance with the clinical use. autoantibodies, however, is indicated, mechanism of action of eculizumab on because positive results may dictate the terminal pathway activation. How- Eculizumab need for additional immunosuppres- ever, in a series of 32 patients with Eculizumab (Soliris; Alexion Pharmaceut- sion. Whether patients with DEAP-HUS biopsy-proven DDD, sMAC was ele- icals) is a recombinant, fully humanized respond better to immunosuppression, vated in only 3 (9%) patients.44 Because mAb that binds with high affinity to the eculizumab, or the combination of both C3 glomerulopathies are mainly charac- humanC5complementproteinandeffi- has yet to be assessed. terized by persistent fluid–phase C3 con- ciently blocks C5 cleavage, regardless of the Approximately 15% of patients with vertase activity without predominant upstream trigger. It thwarts propagation of aHUS are refractory to eculizumab. It is contribution of the terminal comple- the terminal complement cascade and currently unclear whether this is caused ment pathway, eculizumab may not be generation of the membrane attack com- by a mutation in C5, thereby rendering the therapy of choice in the majority of plex. Because it also prevents the genera- eculizumab ineffective (as shown in patients. This was shown in a patient tion of the powerful anaphylatoxin C5a paroxysmal nocturnal hemoglobin- with a C3 glomerulopathy caused by a and subsequent leukocyte infiltration, it uria108) to disease dominantly driven hybrid CFHR2/CFHR5 protein resulting has additional anti–inflammatory effects. by C3 convertase cleavage products, or in increased CFH deregulation.48 When Eculizumab may, thus, be expected to be abnormalities in the coagulation cas- eculizumab was added to the serum of (at least partially) effective in any disease cade. the patient, it effectively blocked C5

2924 Journal of the American Society of Nephrology J Am Soc Nephrol 26: 2917–2929, 2015 www.jasn.org BRIEF REVIEW cleavage and sMAC generation but pre- in one of the key regulators may reveal Bacchi V, Gale DP, Goicoechea de Jorge E, fi dictably, had no effect on the hyperfunc- itself as childhood C3 glomerulopathy or Grif n G, Harris CL, Holers VM, Johnson S, Lavin PJ, Medjeral-Thomas N, Paul 48 fi tioning C3 convertase. aHUS. However, rather than a speci c Morgan B, Nast CC, Noel LH, Peters DK, single defect, more than one genetic Rodríguez de Córdoba S, Servais A, Sethi Inhibition of the C3 Convertase predisposition commonly underlies AP S, Song WC, Tamburini P, Thurman JM, Conceptually, complement inhibition at dysregulation. Novel amino acid epi- Zavros M, Cook HT: C3 glomerulopathy: – the level of the C3 convertase or its topes may be exposed and facilitate the Consensus report. Kidney Int 84: 1079 1089, 2013 components should be effective in any formation of autoantibodies against reg- 4. Sethi S, Fervenza FC: Pathology of renal disorder driven by dysregulation of the ulatory proteins. Triggering factors diseases associated with dysfunction of the C3 convertase, particularly in diseases disrupt the fragile balance between acti- alternative pathway of complement: C3 glo- caused by a stabilized C3 convertase. vation and restraint, thereby instigating merulopathy and atypical hemolytic uremic However, the benefits of upstream in- sustained and inordinate activation of syndrome (aHUS). Semin Thromb Hemost 40: 416–421, 2014 hibition of the complement cascade must the AP. Such considerations account for 5. Bomback AS, Appel GB: Pathogenesis of be weighed against the potential of sig- the varied presentations that include the C3 glomerulopathies and reclassification nificant adverse effects, especially those atypical postinfectious GN, adult C3 of MPGN. Nat Rev Nephrol 8: 634–642, that pertain to the critical role of C3b in glomerulopathy, or aHUS. 2012 innate immunity. The new level of understanding of AP 6. Sethi S, Fervenza FC, Zhang Y, Zand L, Meyer NC, Borsa N, Nasr SH, Smith RJ: Compstatin, a synthetic peptide that pathophysiology heraldsaparadigm shift fi Atypical postinfectious glomerulonephritis potently binds to C3 and its active in the classi cation of these disorders. is associated with abnormalities in the al- fragment C3b, is currently in clinical Traditional clinical assessment and renal ternative pathway of complement. Kidney development for age–related macular pathology are not sufficiently informa- Int 83: 293–299, 2013 degeneration and paroxysmal nocturnal tive to guide us in treatment decisions. In 7. Ramadass M, Ghebrehiwet B, Smith RJ, Kew RR: Generation of multiple fluid-phase C3b: 116 fi hemoglobinuria. Recently described this review, we have de ned pathophys- plasma protein complexes during comple- is an mAb that binds C3b (but not native iologic categories with mechanistic and ment activation: Possible implications in C3 C3), thereby preventing the formation of therapeutic significance. When the clin- glomerulopathies. J Immunol 192: 1220– the C3 convertase (and the generation of ical history or renal biopsy hints at a 1230, 2014 iC3b); indeed, this antibody blocks C3 disorder of complement regulation, a 8. Couser WG, Johnson RJ: The etiology of – glomerulonephritis: Roles of infection and cleavage induced by a C3Nef stabilized biochemical analysis of the different autoimmunity. Kidney Int 86: 905–914, 116 C3 convertase. steps in the complement cascade and a 2014 Another potential approach to com- complete genetic workup should be 9. Pérez-Caballero D, González-Rubio C, plement inhibition is the creation of performed. Deciphering the relative Gallardo ME, Vera M, López-Trascasa M, soluble recombinant forms of comple- pathologic role of the genetic and envi- Rodríguez de Córdoba S, Sánchez-Corral P: Clustering of missense mutations in the ment regulatory proteins. Complement ronmental factors can direct therapy to fi C-terminal region of factor H in atypical he- receptor 1 (CR1) regulates both the C3 the site of dysregulation. As speci cally molytic uremic syndrome. Am J Hum Genet and C5 convertases and is the only co- targeted anticomplement molecules be- 68: 478–484, 2001 factor of CFI that can cleave iC3b into come increasingly available, tailored 10. Boels MG, Lee DH, van den Berg BM, Dane smaller fragments (C3c and C3dg).117 A therapy to shift complement back into MJ, van der Vlag J, Rabelink TJ: The endothelial glycocalyx as a potential modifier of soluble form of CR1 prevented dysregu- balance will truly become feasible. the hemolytic uremic syndrome. 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