Original©2013 Dustri-Verlag Dr. K. Feistle

ISSN 0301-0430

DOI 10.5414/CN108057e-pub: ■■month, ■■day, ■■year

Received April 2, 2013; accepted in revised form May 21, 2013

Correspondence to Carla Nester, MD, MSA, Assistant Professor, Director Pediatric Glomerular Disease Clinic, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, BT 4036, Iowa City, IA 52242-1081, USA carla-nester@uiowa.edu

Key wordsC3 glomerulopathy – alternate pathway of complement – C3 glomerulonephritis – dense deposit disease – membranoproliferative glomerulonephritis

Diagnosis and treatment of C3 glomerulopathyCarla M. Nester1,2,3 and Richard J. Smith1,2,3

1Molecular Otolaryngology and Renal Research Laboratories, 2Department of Internal Medicine and Pediatrics, Divisions of Nephrology, and 3Rare Renal Disease Clinic, Carver College of Medicine, University of Iowa, Iowa City, IA, USA

Abstract. Purpose of review: The purpose of this review is to summarize our current un-derstanding of the principal characteristics of C3 glomerulopathy as a framework for patient evaluation with the goal of setting the stage for a mechanistic approach to treatment. We also review published treatment experience and comment on future initiatives to devise treatment protocols for this rare renal disease patient population. Diagnosis and treatment: Both animal and human data support the role of the alternative pathway of complement in the C3 glomerulopathies. The finding of dominant C3 deposition on renal biopsy, a marker of aberrant complement activity and the primary diagnostic criterion, defines C3 glomerulopathy as a group of diseases that despite variable light and electron microsco-py appearance, shares important phenotypic characteristics; namely the presence of genet-ic mutations in complement genes, the pres-ence of C3 nephritic factors with or without other complement protein abnormalities, and finally a substantial risk for both end-stage renal disease (ESRD) and recurrence after renal transplant. Traditional immune suppres-sive treatment strategies are often ineffective in this group of patients. Case reports and a single small trial support the efficacy of an-ti-complement therapy in this setting. Sum-mary: The diagnosis of C3 glomerulopathy is established by renal biopsy and requires a C3 dominant pattern on immunofluorescence in a patient with active glomerulonephritis. Labo-ratory studies characterizing an individual pa-tient’s complement profile form the basis of an expanded phenotype that has the potential to inform not only the relative activity of dis-ease, but also the risk for adverse outcome or treatment nonresponse. Understanding an in-dividual patient’s complement pathology will facilitate an optimal therapeutic approach to their disease.

Introduction

C3 glomerulopathy (C3G) is the new designation for the group of glomerular

diseases that are characterized by a domi-nant C3 immunofluorescence (IF) pattern on renal biopsy. An underlying assumption, though not part of the formal definition, is that as a group, these diseases are mecha-nistically related to an aberrantly function-ing alternate pathway of complement. The full spectrum of morphological lesions that present as C3G remains to be determined, however a specific light microscopic pattern is not a part of the disease definition (i.e., patients may or may not have a membrano-proliferative pattern on renal biopsy). Just as importantly, it is now accepted that there may be small amounts of immunoglobu-lin present provided the C3 IF intensity is twofold or higher than the immunoglobulin intensity. The original definition of isolated C3 was amended to dominant C3 when a re-view of the literature revealed that even well characterized dense deposit disease (DDD) patients (i.e., the easiest C3G to recognize) with clear electron microscopy (EM) find-ings facilitating an unquestioned diagnosis may have small amounts of immunoglobu-lin on IF (IgG, A and M in 26.7%, 13.3% and 36.7%, respectively) [1].

Two major subgroups of C3G exist and these subgroups are resolved by EM: DDD, defined by the EM findings of intramembra-nous glomerular basement membrane dense deposits [2] and C3 glomerulonephritis (C3GN), encompassing the remainder of the C3G lesions and defined by some combina-tion of subepithelial, subendothelial and/or less dense, discontinuous intramembranous deposits not characteristic of DDD [3]. An-other term often associated with C3G is that of CFHR5 nephropathy, a subcategory of C3GN caused by a genetic rearrangement in CFHR5 that leads to an abnormal protein product [4, 5, 6].

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There are many overlapping characteris-tics between DDD and C3GN, with the pri-mary association being dysregulation of the alternative pathway of complement. C3G pa-tients have in common mutations in alternate complement pathway genes, the presence of C3 nephritic factors and a substantial risk for both ESRD and recurrence of disease after renal transplant (Figure 1). It remains to be seen if the similarities amongst the C3Gs support a common therapeutic strategy or whether differences in pathology will neces-sitate disparate therapeutic approaches.

Complement pathology in C3G

Both animal data and human data support the role of the alternate complement pathway in the pathogenesis of C3G [5, 7, 8, 9, 10, 11, 12, 13, 14]. To understand the pathology behind C3G, it is useful to review the com-plement system and its major components. Figure 2 depicts the three complement path-ways and their relationship to each other. The convertases (common to all of the pathways, though made of slightly different protein constituents) are the key enzymes central to the complement pathways. C3G occurs as a result of dysregulation of the alternate pathway of complement C3 convertase (pink box) and/or the C5 convertase (green box).

The C3 convertase (C3bBb) is the enzyme central to the amplification phase of the complement system. Once the C3 conver-tase is formed (after cleavage of C3 to C3b, C3b combines with Bb, the active cleavage partner of complement factor B to form the C3bBb), it feeds back to cleave C3, and in a circular fashion leads to more C3b and hence more C3 convertase. This amplification loop and its potential to generate massive amounts of C3b results in a highly active complement system that if left unchecked has at least three consequences: 1) increased availabil-ity of anaphylotoxins (C3a and C3b); 2) in-creased activity of the terminal complement pathway (through the generation of C5 con-vertase) with subsequent production of the membrane attack complex (MAC); and 3) increased production of inactivated C3 by-products (iC3b). Homeostasis requires that the protein regulators of complement activa-tion (RCA) are present and functioning prop-erly in the fluid phase (i.e., in circulation as opposed to at the surface of tissues) in order to control the aforementioned processes and prevent these consequences and unintended host damage. In the absence of fluid phase control, C3G results, with glomerular depo-sition of C3b, C3b inactivation products and terminal complement proteins which are re-solved as the EM densities in both DDD and C3GN [15].

Driving the disease-causing complement dysregulation are genetic variants in comple-ment regulatory proteins and autoantibodies to the convertases [5, 9, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. Mutations have been reported in complement Factor H (CFH), complement Factor I (CFI), MCP (also termed membrane cofactor protein or CD46), complement Fac-tor B (CFB) and CFHR5. The relative dis-tribution of rare and novel variants between DDD vs. C3GN is minimal, as demonstrated in a large French cohort (CFH 17.2% vs. 12.5%, CFI 0% vs. 5.3%, and MCP 0% vs. 1.8%) [10]. However, as mentioned earlier, a specific type of C3GN termed CFHR5 ne-phropathy has been described in a large Cy-priot cohort (91 patients and 61 families) [5, 30]. Gain-of-function mutations have also been reported in CFB [30] and complement Factor C3 (C3) [14].

Figure 1. The spectrum of C3 dominant glomeru-lonephritis. C3 dominant glomerulonephritis is a pathological lesion that may appear to include post-infectious glomerulonephritis (PIGN), which must be ruled out before assigning a diagnosis of C3G. C3 dominant glomerulonephritis is the morphological finding in C3G, a disease superclass that is com-prised of two major subclasses: C3GN and DDD. C3Nefs are more common in DDD than in C3GN. Genetic mutations may be more likely in C3GN than in DDD. For both diseases, the relative risk for ESRD is nearly equal, but is unlikely in PIGN, which is a much more common event.

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Dx and Tx of C3G 3

While it is important to recognize that specific “disease-causing” variants may be found and may direct therapeutic decisions as more complement therapeutics become available, what is far more common in the C3G patient is an enrichment for certain al-leles (variations) of the protein components of the complement system. This group of so-called “risk alleles” has been referred to as the C3G “complement haplotype” or “com-plotype”. Even in controls, this complotype is associated with increased basal activity of the complement cascade, and thus this ge-netic background may predispose to C3G in association with a “triggering” environmen-tal insult [12]. The best studied of these risk alleles is the including H402 variant of CFH [31, 32].

As common as risk alleles in C3G pa-tients are autoantibodies called C3 nephritic

factors (C3Nefs) that stabilize the C3 con-vertase. C3Nefs render C3 convertase resis-tant to control by Factor H thereby leading to fluid phase convertase dysregulation. Why C3Nefs develop and whether their de-velopment reflects molecular mimicry and has any relationship to the C3G complotype is not known. However, C3Nefs are very common and are reported in over 80% of patients with DDD [10] and ~ 50% of pa-tients with C3GN [10]. It is extremely im-portant to emphasize that there are many dif-ferent C3Nef assays (ELISA is the LEAST sensitive) and the absence of a C3Nef only means that a nephritic factor was not de-tected by that particular assay and NOT that C3Nefs are absent. We would recommend testing both for the antibody (an IgG-based assay) and its consequence (looking for C3 breakdown products) [33].

Figure 2. The complement cascade. The three phases of complement activation are shown. In the C3Gs, dysregulation occurs at the level of both the C3 and C5 convertases (C3bBb, pink box; C3bBbC3b, green box). The C3 convertase is integral to the amplification phase of complement, with cyclic amplification to generate huge amounts of C3bBb (the C3 convertase) being the default outcome once complement has been activated through any of the three initiating pathways (alternative, mannose-binding lectin, classical). Numerous regulators of complement activation (RCA) proteins are present to control this process and prevent unintended complement damage to the host. The C5 convertase is nearly identical to the C3 con-vertase and is formed from the C3 convertase by the addition of another C3b (the C5 convertase is C3bBbC3b). In C3G, control mechanisms to regulate complement fail in the fluid phase. The consequent dysregulation of the C3 convertase can be measured in patients with C3G by quantitating C3 breakdown products (iC3b, C3c, C3dg, etc.); C5 convertase dysregulation can be quantitated by measuring soluble MAC (sMAC) (see Figure 3). The black arrow points to an antibody that represents eculizumab. Eculi-zumab binds to C5 and prevents its cleavage by the C5 convertase to C5a and C5b. Note that eculizumab has no effect on more proximal dysregulation at the level of the C3 convertase. The green dashed line oval represents the complement pathway activity that would be inhibited by a C3 convertase inhibitor.

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Presentation

The clinical presentation of C3G, with few exceptions, appears to be similar regardless of the subcategory. Much of the phenotypic data comes from two large European cohorts (French [10] and Cypriot [5]) with confirma-tion from the smaller US cohorts [10, 25, 34]. The male-to-female ratio is essentially equal between the two groups, however the age at presentation is higher for C3GN than for DDD (30.3 ± 19.3 vs. 18.9 ± 17.7) [10]. Hematuria occurs in the large majority of pa-tients (range 64.3 – 75.8%) consistent with C3G being a primary glomerular disease. Proteinuria is also common and is frequently in the nephrotic range. The proteinuria range is slightly lower for C3GN than for DDD (3.6 g ± 3.3 vs. 5.6 ± 4.5). A low serum complement C3 is frequently present (59% in DDD and 40% in C3GN), however, is not a requirement for diagnosis.

In light of the presenting characteristics of C3G, post infectious glomerulonephritis (PIGN) may confound the initial diagnosis. PIGN also presents with hematuria, protein-uria and often a low serum complement C3. Furthermore, on renal biopsy, the IF pattern may be that of isolated or dominant C3 stain-ing consistent with the definition of C3G. Distinction from C3G will depend on the absence of atypical features on light micros-copy and EM, and/or on whether the clinical course is typical or atypical for PIGN. How-ever, it is possible that an intercurrent infec-tion, such as one caused by a streptococcal organism, may be a trigger for C3GN when that infection occurs in a person with a C3G-predisposing genotype [35]. We recommend that when presented with a C3 dominant re-nal biopsy and confusion over whether the pathology should be considered PIGN or C3G (i.e., our current understanding of the pathology fails to distinguish the two), the C3G diagnosis should only be assigned if the serum C3 fails to normalize by 12 weeks.

Another confounding diagnosis is the presentation of a DDD lesion in an elderly patient with a monoclonal gammopathy [36, 37]. The current assumption is that the monoclonal protein plays a role in the pa-thology of DDD, however there are only limited data to support this cause-and-effect relationship [35]. Nevertheless, the evalu-

ation and treatment of DDD in this setting should be directed at the monoclonal protein (i.e., through hematological therapies) with the assumption that resolution of the mono-clonal gammopathy may lead to resolution of the glomerular lesion of DDD.

Recovery from the acute presentation of C3G is unpredictable. Ten year native renal survival for this group of patients appears to be between 50 – 60% with young females having the greatest risk for renal failure [34]. In transplant recipients, Lu et al. [34] report-ed a 45% renal allograft loss within 5 years of transplant, data confirmed by Servais et al. [6] in their study reporting the graft loss to be 51%. Interestingly, in CFHR5 nephropathy, men are more likely to develop chronic renal failure (80%) than women (21%) and prog-ress to ESRD (78% vs. 22%). From these data, it is clear that C3G is not a benign dis-ease in the majority of patients.

Treatment

Measures designed to support the pa-tient’s general health (appropriate nutrition, blood pressure control and chronic kidney disease management) are appropriate in pa-tients with C3G. Extrapolating from other glomerular diseases, the angiotensin con-verting enzyme inhibitors or angiotensin re-ceptor blockers should be consider for sup-portive care either for blood pressure control or as an aid to urine protein management. Limited C3G specific data on ACEI or ARB use is offered by the French C3G cohort (a retrospective review) where the use of an-giotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a better renal survival (p < 0.0001) [10]. Similarly, lipid lowering agents are likely to be useful as needed in C3G [38].

There are no good data to support the use of plasmatherapy as a matter of routine care in C3G patients however some case reports do support its efficacy particularly when there is a known protein abnormality. For example, Licht et al. [20] reported efficacy of plasma therapy in a sibling pair with C3G caused by homozygosity for an in-frame amino acid deletion in factor H that compro-mises its RCA function. Plasmatherapy has also been reported to be efficacious in the setting of DDD and acute kidney injury [39,

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40]. Unfortunately plasma therapy failures are also reported even when C3Nefs have been removed by this treatment [41]. These data suggest that in select cases, plasma-therapy may play a role, however, it should be used in the context of a complete patient evaluation with the appropriate biomarker follow-up to determine whether an expected outcome is observed.

Anticellular immune suppression is likely to be entertained early when consid-ering treatment options for C3G (steroid, mycophenolate mofetil, rituximab, cyclo-phosphamide, etc.). The theoretical benefit to traditional anti-cellular therapy includes limiting the effects of the anaphylotoxins (such as C3a and C5a), inhibiting immune cell reaction or inflammation, and/or reduc-ing antibody production. However, the data to support the successful use of anticellular immune suppression are disappointing. Re-ferring to the larger French cohort [10], the use of such agents offered no renal survival advantage to C3G patients. Steroids have been used in this setting perhaps more than any other agent, however their success rate is also hard to substantiate through a review of the literature: Daina et al. [42] reported a failure to induce a remission of DDD despite a prolonged course of steroids. Combina-tions of anticellular drugs have also had lim-ited success: McCaughan et al. [41] reported a failure to respond to glucocorticoid, my-cophenolate mofetil and rituximab therapy. Similarly, Bomback et al. [25] reported the failure of multiple anticellular immune sup-pressive agents in their group of patients.

As data implicating complement dys-regulation in C3G have become more robust, clinicians have turned to anti-complement therapy as a potential directed therapy. C3G complement blockade disease response has been predicted by animal models [8, 43, 44] and there are now multiple reports describ-ing the efficacy of eculizumab as an anti-C5 therapy in C3G. This agent was seen to miti-gate disease in three case reports and in one small trial [25, 41, 42, 45].

Vivarelli et al. [45] reported the case of a 17-year-old female with a 7-year history of DDD (40% glomerular sclerosis on renal biopsy) and normal renal function. She was started on eculizumab when she developed a worsening of nephrotic-range proteinuria.

After 18 months of therapy, she had a re-markable improvement in her urine protein. Importantly, when eculizumab was stopped, she had a recrudescence of her urine protein and a re-induction of a relative remission with the restart of eculizumab. Two subse-quent renal biopsies showed a progressive reduction of C3 and C5b-9 immunefluores-cence and a progressive reduction in mesan-gial proliferation and glomerular capillary loop thickness – each suggestive of a lim-ited histological recovery of the DDD lesion [45]. This finding is consistent with animal data: the clearance of C3 fragments from glomeruli in CFH-deficient mice through the restoration of complement regulation sug-gests that the initial process leading to C3 glomerulopathy is dynamic and may be re-versible [8, 43].

Daina et al. [42] reported the case of a 22-year-old female with DDD and a long-standing history of nephrotic syndrome unre-sponsive to the prolonged use of steroids and rituximab. Her laboratory values included a low C3, the presence of a C3Nef, and an el-evated terminal complement complex. After 48 weeks of eculizumab, this patient’s serum albumin normalized and her creatinine de-creased.

McCaughan et al. [41] reported the ef-ficacy of eculizumab in a case of recurrent DDD post-renal transplant in a 29-year-old female 4 weeks post-operatively (heralded by 6g of urine protein). This recurrence de-veloped while on the standard transplant immune suppression of prednisone, myco-phenolate mofetil and tacrolimus. At the time of recurrence, the patient had a low C3 and a positive C3Nef, and despite rituximab therapy and plasmapheresis (with normaliza-tion of her C3Nef) she continued to progress. Thirteen weeks after transplant, she was started on eculizumab and her creatinine im-proved from 4.9 3mg/dl to 1.9 mg/dl.

Finally, a single trial demonstrating ef-ficacy of eculizumab in some patients with C3G has also been published. Bomback et al. [25] performed an open-label, proof-of-con-cept, efficacy-and-safety study in which they treated 3 DDD (1 with a renal transplant) and 3 C3GN patients (2 with a renal transplant) with eculizumab for 1 year. All had protein-uria > 1 g/d and/or AKI at enrollment. Genetic and complement function testing revealed a

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mutation in CFH and MCP in 1 subject each and C3Nefs in 3 subjects. After 12 months of therapy 2 subjects showed significantly re-duced serum creatinine, 1 subject achieved marked reduction in proteinuria, and one sub-ject had stable laboratory parameters but was noted to have a histopathologic improvement. The patients that responded to eculizumab were those patients who had elevated terminal complement activity as represented by an ele-vated MAC (surveillance of this patient group is ongoing.)

Provided we have a replication of this finding in a broader array of patients, the

finding that responders to eculizumab in the study by Bomback et al. [26] were those with an elevated soluble MAC will be im-portant to the rational use of this therapeutic option. Eculizumab binds C5 and prevents C5 convertase cleavage of C5 to C5a and C5b. The direct result of this blockade is a decreased production of soluble MAC and therefore eculizumab is likely to be most ef-fective in patients with severe dysregulation at the level of C5 convertase as measured by an elevation in soluble MAC. As mentioned in the complement pathology section, C3G patients are likely to have varying degrees of

Figure 3. Complement evaluation and treatment of C3 glomerulpoathy. 1Isolated C3 staining on renal biopsy immune fluorescence or a C3 intensity ≥ 2 orders of magnitude more than any other immune re-actant on a scale of 0 to 3 (including 0, trace, 1+, 2+, 3+). Includes either dense deposit disease (DDD) or C3 glomerulonephritis (C3GN); collectively referred to as the C3 glomerulopathies (C3Gs). 2Failure of C3 to normalize by 12 weeks and/or other atypical clinical features inconsistent with a usual postin-fectious glomerular syndrome. 3Patients with C3G associated with a monoclonal spike or a monoclonal gammopathy of unknown significance should be treated as a separate category. The preferred treatment at this time should be directed at the underlying hematologic abnormality. 4iC3b, C3c, C3dg, desArgC3a; 5desArgC5a; 6Soluble membrane attack complex (soluble C5b-9, sMAC). 7Whether there is a place for blocking anaphylatoxin production to ameliorate glomerular disease remains unclear, however such a block may provide added benefit to anti-complement therapy. It may also be the case that anti-complement therapy would suffice as the sole therapeutic intervention regardless of etiologic agent of the C3G. Italics represent experimental therapies. 8Not currently available; its use would necessitate genetic testing and functional assays of complement activity to confirm functional deficiency of FH. FHAA = complement factor H autoantibody; FBAA = complement factor B autoantibody; FH = complement factor H; FB = complement factor B; FHR = complement factor H related protein; MCP = membrane cofactor protein, etc.

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dysregulation at the level of both the C3 and C5 convertases and so depending on the de-gree of C3 dysregulation that is present, sup-pression of the terminal complement cascade may not be enough to facilitate remission. For example, data from the Cfh–/– mouse, a model of C3GN suggests that while anti-C5 therapy reduces inflammation and urine pro-tein, it does not prevent C3 deposition along the glomerular basement membrane [43]. Therefore laboratory tests must evaluate both the potential for dysregulation at the level of the C3 convertase and the C5 convertase. Optimal treatment should then follow based on the findings of this dual evaluation.

Treatment strategy

The C3G Consensus Group will soon publish its recommendations on the labo-ratory studies that should be considered in order to fully evaluate a C3G patient. These recommendations are a direct result of both our current understanding of the pathol-ogy of C3G (both DDD and C3GN) and the availability of meaningful complement bio-markers. Based on a complete serologic and genetic assessment of the C3G patient, we believe that it may be possible to devise a successful treatment plan for individual pa-tients. The overall intent is to match the com-plement abnormality to a treatment approach specific to that abnormality when such treat-ments are available. We have depicted this strategy in Figure 3.

Plasma therapy should be considered when abnormal proteins are present with plasma infusion (and/or pharmaceutical grade protein factors where available) being preferred for those patients with known fac-tor deficiencies. Anti-cellular therapy may be used to augment the treatment response in this setting. Based on our current under-standing of the pathology of C3G and the published successes we have included anti-complement therapy in our algorithm for treating C3G recognizing that additional trial data are required. Based on the mechanism of the currently marketed anti-complement agent (eculizumab) and the limited trial data, this therapy is best suited for those patients with an elevated terminal complement com-plex assay.

Conclusions

G3G is a new category of glomerular disease characterized by predominant C3 immune deposits on the renal biopsy of a patient with active glomerular disease. Dys-regulation of the alternative and terminal complement pathways either as a result of genetic mutation or acquired autoantibod-ies (or both) is well described as the disease mechanism in both animal and human stud-ies. The full spectrum of the pathological characteristics of C3G has yet to be defined. Advances in our understanding of the role of complement in C3G has improved our ability to characterize the complement phe-notype in individual patients. A more robust understanding of the natural history of C3G will develop as we continue to collect well-described cases, preferably in the form of a registry.

The recent availability of an anti-com-plement agent has allowed us to reconsider our therapeutic options. Undoubtedly, a combination of clinical presentation, renal morphology, genetic workup and comple-ment abnormality assessment will allow for the most efficacious treatment. In addition, as we advance our understanding of comple-ment abnormalities in this setting, we will be able to take advantage of future therapeutic options.

Questions that remain to be answered: Can we further define complement profiles specific to DDD and C3GN? How frequently will PIGN cases be reassigned to C3GN? What are the other triggers for C3Gs? Will a more precise delineation of complement abnormalities in C3G allow for tailored personal anti-complement therapy as more treatment options become available? Will a better understanding of the morphological characteristics of a patient’s biopsy predict treatment response?

As these questions are answered, new questions will arise, especially focused on longevity of treatment. For instance, once a treatment plan is undertaken, how long should patients be treated? A corollary to this, is C3GN or DDD, a relapsing and re-mitting disease or is it persistent, slowly progressive in all patients therefore neces-sitating ongoing therapy? Does treating the anaphylatoxin response offer therapeutic

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advantage over simply blocking the terminal complement cascade or limiting the produc-tion of C3 breakdown products? Would “up-stream” (C3 convertase) inhibitors offer a therapeutic advantage over terminal comple-ment blockade?

Taking advantage of the current interest and focus on C3G, both complement sci-entists and clinicians have the opportunity through rigorous and meticulous study to facilitate improved health for these patients.

Conflict of interest

Dr. Nester is a participant on the C3 Glo-merulopathy Advisory Board, sponsored by Alexion, Inc. Dr. Nester and Dr. Smith col-laborate with Celldex on an investigator ini-tiated study utilizing anti-complement thera-py in dense deposit disease patients.

References[1] Nasr SH, Valeri AM, Appel GB, Sherwinter J,

Stokes MB, Said SM, Markowitz GS, D’Agati VD. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol. 2009; 4: 22-32.

[2] Walker PD, Ferrario F, Joh K, Bonsib SM. Dense deposit disease is not a membranoproliferative glo-merulonephritis. Mod Pathol. 2007; 20: 605-616.

[3] Smith RJH, Alexander J, Barlow PN, Botto M, Cassavant TL, Cook HT, de Córdoba SR, Hage-man GS, Jokiranta TS, Kimberling WJ, Lambris JD, Lanning LD, Levidiotis V, Licht C, Lutz HU, Meri S, Pickering MC, Quigg RJ, Rops AL, Salant DJ et al; Dense Deposit Disease Focus Group. New approaches to the treatment of dense deposit disease. J Am Soc Nephrol. 2007; 18: 2447-2456.

[4] Gale DP, de Jorge EG, Cook HT, Martinez-Barri-carte R, Hadjisavvas A, McLean AG, Pusey CD, Pierides A, Kyriacou K, Athanasiou Y, Voskarides K, Deltas C, Palmer A, Frémeaux-Bacchi V, de Cordoba SR, Maxwell PH, Pickering MC. Identi-fication of a mutation in complement factor H-re-lated protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet. 2010; 376: 794-801.

[5] Athanasiou Y, Voskarides K, Gale DP, Damianou L, Patsias C, Zavros M, Maxwell PH, Cook HT, Demosthenous P, Hadjisavvas A, Kyriacou K, Zouvani I, Pierides A, Deltas C. Familial C3 glo-merulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedi-grees. Clin J Am Soc Nephrol. 2011; 6: 1436-1446.

[6] Vernon KA, Gale DP, de Jorge EG, McLean AG, Galliford J, Pierides A, Maxwell PH, Taube D, Pickering MC, Cook HT. Recurrence of comple-ment factor H-related protein 5 nephropathy in a re-nal transplant. Am J Transplant. 2011; 11: 152-155.

[7] Pickering MC, Cook HT, Warren J, Bygrave AE, Moss J, Walport MJ, Botto M. Uncontrolled C3 activation causes membranoproliferative glomer-ulonephritis in mice deficient in complement fac-tor H. Nat Genet. 2002; 31: 424-428.

[8] Pickering MC, Warren J, Rose KL, Carlucci F, Wang Y, Walport MJ, Cook HT, Botto M. Preven-tion of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-defi-cient mice. Proc Natl Acad Sci USA. 2006; 103: 9649-9654.

[9] Servais A, Frémeaux-Bacchi V, Lequintrec M, Sa-lomon R, Blouin J, Knebelmann B, Grünfeld JP, Lesavre P, Noël LH, Fakhouri F. Primary glomer-ulonephritis with isolated C3 deposits: a new en-tity which shares common genetic risk factors with haemolytic uraemic syndrome. J Med Genet. 2007; 44: 193-199.

[10] Servais A, Noël LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grünfeld JP, Niaudet P, Lesavre P, Frémeaux-Bacchi V. Ac-quired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 2012; 82: 454-464.

[11] Sethi S, Fervenza FC, Zhang Y, Zand L, Vrana JA, Nasr SH, Theis JD, Dogan A, Smith RJ. C3 glo-merulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up. Kidney Int. 2012; 82: 465-473.

[12] Abrera-Abeleda MA, Nishimura C, Frees K, Jones M, Maga T, Katz LM, Zhang Y, Smith RJ. Allelic variants of complement genes associated with dense deposit disease. J Am Soc Nephrol. 2011; 22: 1551-1559.

[13] Abrera-Abeleda MA, Nishimura C, Smith JL, Sethi S, McRae JL, Murphy BF, Silvestri G, Skerka C, Józsi M, Zipfel PF, Hageman GS, Smith RJ. Varia-tions in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associ-ated with membranoproliferative glomerulone-phritis type II (dense deposit disease). J Med Genet. 2006; 43: 582-589.

[14] Martínez-Barricarte R, Heurich M, Valdes-Cañedo F, Vazquez-Martul E, Torreira E, Montes T, Torta-jada A, Pinto S, Lopez-Trascasa M, Morgan BP, Llorca O, Harris CL, Rodríguez de Córdoba S. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regula-tion. J Clin Invest. 2010; 120: 3702-3712.

[15] Sethi S, Gamez JD, Vrana JA, Theis JD, Bergen HR III, Zipfel PF, Dogan A, Smith RJH. Glomeru-li of Dense Deposit Disease contain components of the alternative and terminal complement path-way. Kidney Int. 2009; 75: 952-960.

[16] Levy M, Halbwachs-Mecarelli L, Gubler M-C, Kohout G, Bensenouci A, Niaudet P, Hauptmann G, Lesavre P. H deficiency in two brothers with atypical dense intramembranous deposit disease. Kidney Int. 1986; 30: 949-956.

[17] Marder HK, Coleman TH, Forristal J, Beischel L, West CD. An inherited defect in the C3 conver-tase, C3b,Bb, associated with glomerulonephritis. Kidney Int. 1983; 23: 749-758.

[18] Linshaw MA, Stapleton FB, Cuppage FE, Forristal J, West CD, Schreiber RD, Wilson CB. Hypocom-

• 108057Nest / 3. July 2013, 10:59 AM

Dx and Tx of C3G 9

plementemic glomerulonephritis in an infant and mother. Evidence for an abnormal form of C3. Am J Nephrol. 1987; 7: 470-477.

[19] Dragon-Durey MA, Frémeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, Coppo P, Herman Fridman W, Weiss L. Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoprolif-erative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol. 2004; 15: 787-795.

[20] Licht C, Heinen S, Józsi M, Löschmann I, Saunders RE, Perkins SJ, Waldherr R, Skerka C, Kirschfink M, Hoppe B, Zipfel PF. Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int. 2006; 70: 42-50.

[21] Habbig S, Mihatsch MJ, Heinen S, Beck B, Emmel M, Skerka C, Kirschfink M, Hoppe B, Zipfel PF, Licht C. C3 deposition glomerulopathy due to a functional factor H defect. Kidney Int. 2009; 75: 1230-1234.

[22] Wu J, Wu YQ, Ricklin D, Janssen BJ, Lambris JD, Gros P. Structure of complement fragment C3b-factor H and implications for host protection by complement regulators. Nat Immunol. 2009; 10: 728-733.

[23] Schejbel L, Schmidt IM, Kirchhoff M, Andersen CB, Marquart HV, Zipfel P, Garred P. Complement factor H deficiency and endocapillary glomerulo-nephritis due to paternal isodisomy and a novel fac-tor H mutation. Genes Immun. 2011; 12: 90-99.

[24] Servais A, Noël LH, Dragon-Durey MA, Gübler MC, Rémy P, Buob D, Cordonnier C, Makdassi R, Jaber W, Boulanger E, Lesavre P, Frémeaux-Bac-chi V. Heterogeneous pattern of renal disease as-sociated with homozygous factor H deficiency. Hum Pathol. 2011; 42: 1305-1311.

[25] Bomback AS, Smith RJ, Barile GR, Zhang Y, Heher EC, Herlitz L, Stokes MB, Markowitz GS, D’Agati VD, Canetta PA, Radhakrishnan J, Appel GB. Eculizumab for dense deposit disease and C3 glo-merulonephritis. Clin J Am Soc Nephrol. 2012; 7: 748-756.

[26] Montes T, Goicoechea de Jorge E, Ramos R, Gomà M, Pujol O, Sánchez-Corral P, Rodríguez de Córdoba S. Genetic deficiency of complement factor H in a patient with age-related macular de-generation and membranoproliferative glomeru-lonephritis. Mol Immunol. 2008; 45: 2897-2904.

[27] Leroy V, Fremeaux-Bacchi V, Peuchmaur M, Bau-douin V, Deschênes G, Macher MA, Loirat C. Membranoproliferative glomerulonephritis with C3NeF and genetic complement dysregulation. Pediatr Nephrol. 2011; 26: 419-424.

[28] Vernon KA, Pickering MC, Cook T. Experimental models of membranoproliferative glomerulone-phritis, including dense deposit disease. Contrib Nephrol. 2011; 169: 198-210.

[29] Heurich M, Martínez-Barricarte R, Francis NJ, Roberts DL, Rodríguez de Córdoba S, Morgan BP, Harris CL. Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk. Proc Natl Acad Sci USA. 2011; 108: 8761-8766.

[30] Strobel S, Zimmering M, Papp K, Prechl J, Józsi M. Anti-factor B autoantibody in dense deposit disease. Mol Immunol. 2010; 47: 1476-1483.

[31] Skerka C, Lauer N, Weinberger AA, Keilhauer CN, Sühnel J, Smith R, Schlötzer-Schrehardt U, Fritsche L, Heinen S, Hartmann A, Weber BH, Zipfel PF. Defective complement control of factor H (Y402H) and FHL-1 in age-related macular de-generation. Mol Immunol. 2007; 44: 3398-3406.

[32] Laine M, Jarva H, Seitsonen S, Haapasalo K, Lehtinen MJ, Lindeman N, Anderson DH, Johnson PT, Järvelä I, Jokiranta TS, Hageman GS, Im-monen I, Meri S. Y402H polymorphism of comple-ment factor H affects binding affinity to C-reactive protein. J Immunol. 2007; 178: 3831-3836.

[33] Zhang Y, Meyer NC, Wang K, Nishimura C, Frees K, Jones M, Katz LM, Sethi S, Smith RJH. Causes of alternative pathway dysregulation in dense deposit disease. Clin J Am Soc Nephrol. 2012; 7: 265-274.

[34] Lu DF, Moon M, Lanning LD, McCarthy AM, Smith RJ. Clinical features and outcomes of 98 children and adults with dense deposit disease. Pediatr Nephrol. 2012; 27: 773-781.

[35] Sethi S, Fervenza FC, Zhang Y, Zand L, Meyer NC, Borsa N, Nasr SH, Smith RJH. Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement. Kidney Int. 2013; 83: 293-299.

[36] Sethi S, Sukov WR, Zhang Y, Fervenza FC, Lager DJ, Miller DV, Cornell LD, Krishnan SGS, Smith RJH. Dense deposit disease associated with monoclonal gammopathy of undetermined signif-icance. Am J Kidney Dis. 2010; 56: 977-982.

[37] Sethi S, Zand L, Leung N, Smith RJH, Jevremonic D, Herrmann SS, Fervenza FC. Membranoprolif-erative glomerulonephritis secondary to monoclo-nal gammopathy. Clin J Am Soc Nephrol. 2010; 5: 770-782.

[38] Maisch NM, Pezzillo KK. HMG-CoA reductase inhibitors for the prevention of nephropathy. Ann Pharmacother. 2004; 38: 342-345.

[39] Banks RA, May S, Wallington T. Acute renal fail-ure in dense deposit disease: recovery after plas-mapheresis. Br Med J (Clin Res Ed). 1982; 284: 1874-1875.

[40] Krmar RT, Holtbäck U, Linné T, Berg UB, Celsi G, Söderberg MP, Wernerson A, Szakos A, Larsson S, Skattum L, Bárány P. Acute renal failure in dense deposit disease: complete recovery after combina-tion therapy with immunosuppressant and plasma exchange. Clin Nephrol. 2011; 75 (Suppl 1): 4-10.

[41] McCaughan JA, O’Rourke DM, Courtney AE. Re-current dense deposit disease after renal trans-plantation: an emerging role for complementary therapies. Am J Transplant. 2012; 12: 1046-1051.

[42] Daina E, Noris M, Remuzzi G. Eculizumab in a patient with dense-deposit disease. N Engl J Med. 2012; 366: 1161-1163.

[43] Fakhouri F, de Jorge EG, Brune F, Azam P, Cook HT, Pickering MC. Treatment with human com-plement factor H rapidly reverses renal comple-ment deposition in factor H-deficient mice. Kid-ney Int. 2010; 78: 279-286.

[44] Paixão-Cavalcante D, Hanson S, Botto M, Cook HT, Pickering MC. Factor H facilitates the clear-ance of GBM bound iC3b by controlling C3 acti-vation in fluid phase. Mol Immunol. 2009; 46: 1942-1950.

[45] Vivarelli M, Pasini A, Emma F. Eculizumab for the treatment of dense-deposit disease. N Engl J Med. 2012; 366: 1163-1165.

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