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C3 glomerulopathy: A new complement-based entity
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Rev Clin Esp. 2014;xxx(xx):xxx---xxx
Revista Clínica Española www.elsevier.es/rce
CLINICAL UP-DATE
C3 glomerulopathy: A new complement-based entity夽 A. de Lorenzo ∗ , S. Tallón, B. Hernández-Sevillano, G. de Arriba Servicio de Nefrología, Hospital Universitario de Guadalajara, Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain Received 24 June 2013; accepted 20 January 2014
KEYWORDS C3 glomerulopathy; Dense-deposit disease; Alternative complement pathway; Factor H; Factor I; C3 nephritic factor; Eculizumab
Abstract C3 glomerulopathy is a new, recently described entity that has changed the perspective, treatment and classification of a number of glomerular diseases. It encompasses 2 similar but clearly differentiated pathologies----the dense-deposit disease and C3 glomerulonephritis itself. The alternative complement pathway plays a fundamental role in its pathogenesis and, specifically, the mutations and defects in its regulatory factors (mainly factor H and factor I), as well as the presence of acquired autoantibodies (C3 nephritic factor), which generates an unbridled activation of the system, and ultimately, a deposit of its products at the glomerular level. Its poor prognosis and onset in young populations make the detailed study of new therapeutic alternatives for this disease essential. Recently eculizumab, an anti-C5 antibody, has demonstrated effectiveness in the treatment of these patients. © 2013 Elsevier Espa˜ na, S.L. All rights reserved.
PALABRAS CLAVE
Glomerulopatía C3: una nueva entidad basada en el complemento
Glomerulopatía C3; Enfermedad por depósitos densos; Vía alternativa del complemento; Factor H; Factor I; Factor nefrítico C3; Eculizumab
Resumen La glomerulopatía C3 es una nueva entidad descrita recientemente que ha cambiado la visión, el tratamiento y la clasificación de algunas enfermedades glomerulares. Engloba 2 patologías similares pero claramente diferenciadas: la enfermedad por depósitos densos y la glomerulonefritis C3 propiamente dicha. La vía alternativa del complemento juega un papel fundamental en su patogenia, y en concreto las mutaciones o defectos en sus factores reguladores (fundamentalmente factor H y factor I), así como la presencia de autoanticuerpos adquiridos (factor nefrítico C3) que generan una activación desenfrenada del sistema, y en último término un depósito de sus productos a nivel glomerular. Su mal pronóstico y la aparición en población joven hacen preciso el estudio de nuevas alternativas terapéuticas. Recientemente eculizumab, un anticuerpo anti C5, ha demostrado efectividad en el tratamiento de estos pacientes. © 2013 Elsevier Espa˜ na, S.L. Todos los derechos reservados.
夽 Please cite this article as: de Lorenzo A, Tallón S, Hernández-Sevillano B, de Arriba G. Glomerulopatía C3: una nueva entidad basada en el complemento. Rev Clin Esp. 2014. http://dx.doi.org/10.1016/j.rce.2014.01.016 ∗ Corresponding author. E-mail address: [email protected] (A. de Lorenzo).
2254-8874/$ – see front matter © 2013 Elsevier Espa˜ na, S.L. All rights reserved.
RCENG-908; No. of Pages 9
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The clinical problem Advances in the understanding of alternative complement pathway abnormalities have led to the recent discovery of a new entity in the setting of glomerular diseases. This entity is known as C3 glomerulopathy.1---4 The onset of this new disease makes the classification of membranoproliferative glomerulonephritis obsolete and opens a new field of research in the setting of its treatment using new biological therapies such as the anti-C5 monoclonal antibody eculizumab.
C3 glomerulopathy The term C3 glomerulopathy includes 2 subtypes: densedeposit disease (DDD) and C3 glomerulonephritis (GNC3) itself, 2 entities that have in common the isolated deposit of complement 3 (C3) fraction, i.e., in the absence of immunoglobulins, and which, in turn, have ultrastructural differences that allow them to be differentiated. Alternative complement pathway abnormalities cause the isolated deposit of factor C3 in the mesangium and capillary wall, which is characteristic of membranoproliferative glomerulonephritis and is produced without concomitant immunoglobulin deposit.5,6 The clinical expression is a microscopic hematuria-proteinuria syndrome with a variable degree of proteinuria, which can reach the nephrotic range. If electron-dense deposits visible by electron microscope are identified, then the disease is classified as DDD. If these deposits are absent, the disease is classified as GNC3, in which case the deposits are very similar to those of glomerulonephritis mediated by immune complexes (located at the mesangial, subendothelial, subepithelial and/or intramembranous level), although without them being present.7
A. de Lorenzo et al. Table 1 New classification of membranoproliferative glomerulonephritis. Mediated by immune complexes Infections Autoimmune diseases Neoplasms Gammopathies/dysproteinemias Mediated by complement: C3 glomerulopathy Dense-deposit disease C3 glomerulonephritis Membranoproliferative glomerulonephritis mediated by immune complexes is produced by persistent antigenemia whose resulting immune complex activates the classical complement pathway. Direct immunofluorescence stainings will be positive to immunoglobulins, mainly IgG and IgM, as well as C3 and/or C1. C3 glomerulopathy is produced by dysfunction of the alternative complement pathway (mutations or autoantibodies); its direct immunofluorescence is negative for immunoglobulins but positive for complement (C3).
To confirm a suspected diagnosis, a renal biopsy is essential. Here the diagnostic criterion is the presence of electron-dense deposits in the GBM, along with direct immunofluorescence for C3 and the absence of immunoglobulin deposits in most cases, as well as a reduction in plasma C3 levels, whose levels need to be determined. Once the diagnosis has been confirmed and depending on the availability at each center, a complement study should be requested.11 Approximately 50% of affected individuals progress to end-stage renal disease (ESRD) at 10 years after diagnosis, although the course is more aggressive and rapid in young patients and women.12,13
Dense-deposit disease This is an extremely rare disease (2---3 cases per million) that mainly affects children and young adults and is slightly more common in women (3:2 ratio). Clinically, the disease presents with varying amounts of proteinuria and hematuria. The essential characteristic that defines and differentiates this entity is the presence of electron-dense deposits in the glomerular basement membrane (GBM) and mesangium, and not the presence or absence of a membranoproliferative pattern observed under optical microscopy consisting of the thickening of the GBM along with the proliferation of mesangial cells (which is only present in 25% of affected individuals). The most common histological pattern is mesangial proliferation (45%). For this reason, we can say that the term membranoproliferative glomerulonephritis (MPGN) type II has become obsolete. In fact, MPGN is currently classified as mediated by immune complexes (which include types I and III, caused most often by the hepatitis B and C viruses whose antigenemia causes the depositing of immune complexes at the glomerular level)8---10 and by the complement (DDD and GNC3) (Table 1). Given that there is a deregulation of the alternative complement pathway in the origin of DDD, 60---80% of cases have complement consumption data manifested by low serum levels of C3 and degradation products.
C3 glomerulonephritis The concept of GNC3 was coined in 2007 when Servais et al.1 described what is known as ‘‘primary glomerulonephritis with isolated C3 deposits’’. The fundamental requirement for the diagnosis of this entity, as with DDD, was the isolated deposits of C3 on immunofluorescence. It was noteworthy that these patients had none of the typical characteristics of DDD, and in fact the deposits resembled those of MPGN types I and III, with the significant exception that they lacked immune complexes. Reduced serum C3 levels appear less frequently than in DDD in 40% of cases. There are no major differences in terms of the clinical presentation between DDD and GNC3, although GNC3 has a slightly better prognosis; approximately 20% of patients progress to ESRD at 10 years, and 30% progress to stages 3---4 CKD.1
Etiopathogenesis The complement system is a mechanism mainly involved in defending against infections (mainly gram negative germs) and tumor cells. The system consists of approximately 30 factors that are mostly plasma proteins. Complement activation can be initiated by 3 different pathways (classical,
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C3 glomerulopathy: A new complement-based entity Factor H
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C3
convertasa
+
C3
+ +
C3 nephritic factor
C3b +
Factor I
Alternative pathway
C3i
Terminal cascade
C5
convertase
C5 +
C5b
MAC Figure 1 Alternative complement pathway. In the activation of the alternative complement pathway, C3 convertase cleaves C3 into C3a and C3b, the latter of which is a potent C3 convertase amplifier and generator. This process is regulated by factor H (which inhibits C3 convertase) and factor I (which converts C3b into inactive C3b, thereby slowing the cascade). In addition, C5 convertase is generated from the products derived from the action of C3 convertase. This enzyme cleaves C5 into C5a and C5b. The binding of C5b with C6---C9 forms the membrane attack complex (MAC) with chemotactic activity in the cell surfaces, resulting in cell lysis.
alternative and lectin). It involves changes in particular components that result in chain reactions, in such a way that active products are generated that, in addition to ensuring that the chain continues to the next reaction, can have important biological activities in the body’s defense. All these are due to the fact that most complement factors are proteolytic in nature.14 The alternative complement pathway is generally active in circulation, although at low levels due to regulatory mechanisms that prevent selfharm. There are 2 main regulators of this pathway: factors H and I, whose abnormalities (either inherited or acquired) create an imbalance between activating and inhibiting factors (Fig. 1). DDD and GNC3 have a common etiopathogenic origin in the mutations of the alternative complement pathway. A disorder in the regulation of C3 and C5 convertases generates an unbridled activation of the system and a considerable quantity of C3b and membrane attack complex (MAC), which ends by accumulating in the glomerular capillary wall, ultimately generating C3 glomerulopathy.15 DDD and GNC3 can probably be differentiated by the degree to which one or the other convertase is affected. It seems that in the case of DDD, the predominant disorder is at the C3 convertase level, while the origin of GNC3 is mainly due to a C5 convertase disorder. In recent years, there have been numerous publications on this disease. Several mutations of genes involved in this process of improper activation of the complement have been reported, such as CFHR5, factor H, factor I and factor
3 C3,16---19 although the majority of patients have polymorphisms of several genes. These polymorphisms generate new epitopes that determine the development of autoantibodies known as C3 nephritic factor, which acts as a stabilizer of C3 convertase, preventing the action of physiological regulators such as factor H. Thus, for DDD, 60---80% of cases progress with complement consumption data manifested by low serum levels of C3 and products resulting from its degradation. In GNC3, the percentage of reduced C3 is somewhat lower, appearing in 40% of patients. Sethi et al.20 reported on a series of 12 patients with GNC3 and alternative complement pathway disorder. Initially, 9 of the 12 patients with GNC3 were classified as having MPGN I (n = 4), MPGN III (n = 1) and postinfectious glomerulonephritis (n = 4). The Sethi group showed that the proteomic profile of GNC3 was similar to that of DDD (with a predominance of C3 and final complement pathway components). This result supports the theory that the presence of isolated C3 is the main marker of alternative complement pathway dysfunction in C3 glomerulopathy, regardless of its optical or ultrastructural histology. The greatest contribution from the genotypic and phenotypic points of view has been the data from 2 recently published cohorts. The first, published in 2010 by Gale et al.21 describes 91 patients belonging to 16 families of Cypriot origin with a CFHR5 mutation that encodes protein 5 related to factor H. The mutation was more common in men than in women (80% vs. 21%). In this case, the condition was labeled nephropathy CFHR5, characterized by persistent microscopic hematuria with gross hematuria coinciding with intercurrent upper respiratory infection (imitating the typical presentation of nephropathy by IgA deposits), as well as proteinuria in 38% of the cases, with progression to ESRD more likely in these cases, especially for males (78% vs. 22%).22 In 2012, Servais et al.23 studied a French cohort of 85 patients with C3 glomerulopathy, 56 of them with GNC3 and 29 with DDD. Sixty percent of the patients had microscopic hematuria; the proteinuria levels were slightly lower in the cases with GNC3 than in those with DDD (3.6 ± 3.3 g vs. 5.6 ± 4.5 g). Although both conditions are present in the young population, the patients with GNC3 were older (30.3 ± 19.3 vs. 18.9 ± 17.7 years). These authors were also the first to shed light on the possible etiological origin of GNC3, given that 31% of their patients had a mutation in factor H, factor I or in the membrane cofactor protein. They also observed that C3 nephritic factor was less common in GNC3 than in DDD (45% vs. 86%), which also occurred with reduced serum C3 levels (86.4% vs. 45.3%). Habbig et al.24 reported on a family with 2 siblings of consanguineous parents with hematuria and proteinuria since childhood. Both siblings had reduced levels of serum C3 and complement regulatory factor B. A mesangial deposit of C3 and C5b-9 was observed in the biopsy, and numerous mesangial, intramembranous and subendothelial deposits were observed under electron microscopy. Genetic screening for factor H mutations showed that both children were homozygous for a lysine deletion. This deletion leads to a critical reduction of this cofactor inhibitor. Additionally, both patients and their healthy mother were positive for C3 nephritic factor. In 2010, Martínez-Barricarte et al.25
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A. de Lorenzo et al. Table 2
Case series of C3 glomerulopathy: characteristics, treatment and evolution.
Author
n
Diagnosis
Mutation
C3 nephritic factor
Native kidTreatment ney/transplant
Response/ evolution
Servais et al. (2007)1
19
GNC3
Factor H (n = 3) Factor I (n = 2) MCP (n = 1)
Positive (n = 7)
N
RAASI (n = 8) E (n = 5)
Habbig et al. (2009)24
2
GNC3
Factor H (n = 2)
Positive
N
MartínezBarricarte et al. (2010)19 Darouich et al. (2011)44 Gale et al. (2010)21 Athanasiou et al. (2011)22 Deltas et al. (2013)45 Sugimoto et al. (2012)46
3
DDD
C3
Negative
N (n = 2) T (n = 1)
Fresh plasma infusion ND
1
GNC3
ND
ND
N
ND
ND
Glom.C3
Factor H (CFHR5)
Negative (n = 4)a
N
ND
RF deterioration to ESRD (n = 28)
1
GNC3
Factor H
Negative
N
RAASI
Sethi et al. (2012)20
12
GNC3
Factor H (n = 2) Factor I (n = 1)
Positive (n = 5)
N (n = 10) T (n = 2)
Servais et al. (2012)23
85
GNC3 (n = 56)
Factor H (n = 7) Factor I (n = 3) MCP (n = 1) Factor H (n = 5)
Positive (n = 24)
N and T (number not specified)
RAASI (n = 2) RAASI + E (n = 7) MMF (n = 3) E + CFM (n = 1) RAASI (n = 19) IS (n = 19) RAASI (n = 14) IS (n = 14) Eculizumab
No RF impairment Increased Pr No RF impairment (n = 10). No response (n = 2)
136
DDD (n = 29)b
Positive (n = 19)
McCaughan et al. (2012)31 Bomback et al. (2012)32
1
DDD
No
Positive
T
6
GNC3 (n = 3) DDD (n = 3)
Factor H (n = 1) MCP (n = 1)
Positive (n = 3)
N (n = 3) T (n = 3)
Eculizumab
Vivarelli et al. (2012)38 Daina et al. (2012)39
1
DDD
No
Positive
N
Eculizumab
1
DDD
No
Positive
N
Eculizumab
Gurkan et al. (2013)41
1
GNC3
No
Positive
T
Eculizumab
RF impairment (n = 15), of these ESRDs (n = 5) No disease progression ND
RF deterioration to ESRD (n = 27) RF deterioration to ESRD (n = 23) Reduction of Cr and Pr Reduction of Cr (n = 2) and Pr (n = 1). Increase of Alb (n = 1) Reduction of Pr Increase of Alb Reduction of Cr and Pr Increase of Alb Stable Cr and Pr Histopathologic progression
Alb, plasma albumin; CFM, cyclophosphamide; Cr, plasma creatinine; E, steroids; DDD, dense-deposit disease; ESRD, end-stage renal disease; RF, renal function; Glom.C3, glomerulopathy C3; GNC3, glomerulonephritis C3; RAASI, renin---angiotensin---aldosterone system inhibitors; MMF, mycophenolate mofetil; N, native kidney; ND, not described; MCP, membrane cofactor protein; Pr, proteinuria; and T, kidney transplant. a Measurement performed in 4 patients. b The total number of patients in the series is complete with 41 patients who were diagnosed with type I membranoproliferative glomerulonephritis.
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C3 glomerulopathy: A new complement-based entity
5 Renal biopsy Diverse glomerular histology with/without MPGN pattern
Mesangial proliferation with duplication of the GBM (MPGN pattern)
IF Immunoglobulins with/without C3
Isolated C3
Autoimmune diseases Mediated by immune complexes + classical complement pathway
Infections
Mediated by alternative complement pathway
Gammopathies Dysproteinemias
Electron M. deposits
Mesangial and subendothelial
MPGN type I
Mesangial, subendothelial, subepithelial and/or intramembranous
MPGN type III
Electron M. deposits
Mesangial, subendothelial, subepithelial and/or intramembranous
Mesangial and intramembranous
GNC3
DDD
Figure 2 Classification of membranoproliferative glomerulonephritis. Abbreviations: DDD, dense-deposit disease; GNC3, C3 glomerulonephritis; MPGN, membranoproliferative glomerulonephritis; IF, immunofluorescence; electron M., electron microscope; and GBM, glomerular basement membrane.
published a report on a family with DDD and a C3 mutation. This mutation conferred resistance to C3 against its excision by C3 convertase, thereby preventing the formation of activated C3b. The disease in this family was caused exclusively by dysregulation in the fluid phase of the alternative pathway with no contribution from the terminal complement cascade (TCC). In contrast, the GNC3 described in the Cypriot families by Gale et al.21 and in the siblings by Habbig et al. were associated with the C5 convertase disorder and the subsequent activation of the TCC (Table 2). The alternative complement pathway disorder could also be due to acquired causes that trigger the formation of 2 types of antibodies (Ab), various inhibitors (antifactor H Ab and antifactor I Ab) and others that directly stimulate complement activation such as C3 nephritic factor, an IgG autoantibody that stabilizes C3 convertase, extending its half-life and enzymatic activity.
in relatives with subclinical involvement. Experts recommend measuring serum levels of CH50, C3, C3d, C4, factor H and factor I, studying their mutations, assessing the presence of autoantibodies such as C3 nephritic factor and conducting functional trials of the alternative complement pathway (Fig. 2).20,26,27
Treatment Despite significant progress in the understanding of the underlying mechanisms, advances in treatment have not enabled the development of effective compounds. Various treatment modalities are used with varying degrees of effectiveness. Examples of treatments include renin---angiotensin axis blockade, plasmapheresis with plasma infusion and cellular immunosuppressants. The exception to this rule is biological therapy directed using the anti-C5 monoclonal antibody eculizumab.
Assessment of patients with C3 glomerulopathy
Renin---angiotensin axis inhibitors
In the clinical assessment of patients with C3 glomerulopathy, the identification of the underlying defect in the alternative complement pathway can be very useful. It allows a family study to be carried out and prevents damage
The current evidence on chronic kidney disease and glomerulopathy with nonselective proteinuria, as well as the data obtained by Servais et al.23 in this group of diseases, support the use of angiotensin-converting enzyme inhibitors
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Plasma therapy
Maintenance
Experience with its use is based on individual cases, such as the report by Lich et al.18 of 2 twins diagnosed with DDD and the previously mentioned report by Habbig et al.24 Both cases had factor H deficiency secondary to a mutation and a satisfactory response to factor H repletion achieved using plasma exchange. The direct contribution of this factor could be available for therapeutic use in the near future.30 In other cases, plasmapheresis with replenishment of plasma factors has not been effective, according to the reports by McCaughan et al.31 and Martinez-Barricarte et al.,25 all of which dealt with DDD. Martinez-Barricarte et al. postulated the presence of a C3 convertase mutation that would make it resistant to the inhibitory action of factor H and would therefore hinder the effectiveness of replenishing plasma factor. This would in turn require new specific treatments aimed at restoring control of C3 convertase activity and eliminating C3 degradation products from plasma.20
1200 mg every 2 weeks 900 mg every 2 weeks 600 mg every 2 weeks 300 mg every 2 weeks 300 mg every 2 weeks
Administrationa
(ACEI) and angiotensin II receptor antagonists (ARA II) to preserve renal function in this group of diseases.28,29
240 mL in 30---45 min 180 mL in 30---45 min 120 mL in 30---45 min 60 mL in 30---45 min 60 mL in 30---45 min
6
Administrationa
There is no evidence supporting the use of immunosuppressive therapy in C3 glomerulopathy,3 given that the various lines of treatment have provided highly variable responses and questionable efficacy, as is the case with prednisone and mycophenolate, which have shown no benefit according to the cases reported by Sethi et al.20 and Bomback et al.32 The combination of these agents with biological therapies, such as the antilymphocyte CD20 monoclonal antibody rituximab used by McCaughan et al.,31 was also ineffective in a kidney transplant recipient.
180 mL in 30---45 min 120 mL in 30---45 min 120 mL in 30---45 min 120 mL in 30---45 min 60 mL in 30---45 min
Cellular immunosuppression
Induction
900 mg/week; 4 dose 600 mg/week; 2 dose 600 mg/week; 2 dose 600 mg single dose 300 mg single dose
Weight
>40 kg 30---40 kg 20---30 kg 10---20 kg 5---10 kg
Table 3
Eculizumab is an anti-C5 antibody that impedes the excision of C5 in C5b and decreases the production of C5a, thereby preventing the activation of the terminal cascade and the formation of CAM (Table 3).7 Eculizumab was the first drug that, using this mechanism of action, managed to effectively and safely reduce hemolysis in paroxysmal nocturnal hemoglobinuria. This condition was the first indication for eculizumab in 2008,33 although practically every year new applications and therapeutic indications are being discovered for numerous diseases mediated by the complement, such as atypical hemolytic-uremic syndrome,34 C3 glomerulopathy and HELLP syndrome.35 The most important secondary effect of eculizumab is a direct consequence of the inhibition of the terminal complement cascade, which predisposes patients to infections by encapsulated germs such as Neisseria meningitidis. Vaccinations and antibiotic prophylaxis are therefore recommended at least 14 days before starting treatment with eculizumab.36,37 The first published cases of glomerulonephritis treated with eculizumab31,32,38---41 appeared in the literature in 2012, 6 of them with DDD, 3 with GNC3 and another diagnosed with MPGN I refractory to treatment. Of the 10 patients who
Eculizumab: dosage and method of administration.
Eculizumab
Standard dosage for patients older than 18 years: 900 mg weekly for the first 4 weeks, followed by 1200 mg on the fifth week and subsequent maintenance with 1200 mg every 2 weeks. a 300 mg vials (30 mL) in dilution 5 mg/mL with physiological saline (0.9%, 0.45%) or glucose solution (5%).
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C3 glomerulopathy confirmed by biopsy
Measurement of C3 nephritic factor
+
Serum levels of CH50, C3, C3d, C4, factor H, factor I
Study of factor H and factor I mutations
-
No
Yes
Treatment
Plasmapheresis plasma infusion rituximab
Plasma infusion ACEI ARA II
Eculizumab
Figure 3 Treatment. Treatment regimen based on the findings of the complement functionality and genetics study. Abbreviations: ARA II, angiotensin II receptor antagonists; and ACEI, angiotensin-converting enzyme inhibitors.
underwent the treatment, improved renal function parameters were observed in 8, with 1 patient showing lower glomerulonephritis activity at the histopathological level in a second biopsy. The 2 remaining patients experienced renal function deterioration during the follow-up, 1 of whom eventually required dialysis. It is worth noting that 2 of the patients who responded positively worsened immediately after the use of eculizumab was withdrawn. An association was found between MAC levels prior to treatment and the response to the same; these levels could therefore be useful as a predictive factor. Given the high cost of therapy with this antibody, patient candidates for undergoing this therapy should be selected carefully. A recent review by Zuber et al.42 on the use of eculizumab in atypical hemolytic-uremic syndrome and C3 glomerulopathy suggested that optimal candidates for taking eculizumab would be patients with a recent diagnosis, active inflammatory lesions (crescent formation and endocapillary proliferation) and minimal interstitial fibrosis in the pathology, as well as an increase in serum creatinine and/or proteinuria levels and high serum MAC levels (Fig. 3).32,43
plasma levels of complement regulation factors can provide a criterion for selecting the optimal treatment. The rarity of the disease has precluded the availability of strong evidence, and there are only small series of patients in whom different treatment modalities have been employed. Anticomplement therapy with eculizumab has offered the most promising results so far, although it requires a careful selection of candidates, such as those without no chronicity data in the renal biopsy and with renal function impairment and/or proteinuria, as well as high levels of MAC (when their measurement is possible), because they are associated with a better treatment response. In the case of our patient, electron microscopy of the renal biopsy confirmed the diagnosis of C3 glomerulonephritis. A study was performed of the alternative complement pathway, which showed normal levels of factors I and H, with no abnormal bands in the structural characterization of factor H and the absence of antifactor H antibodies and C3 nephritic factor. The genetic study, however, detected a change in heterozygosity in exon 4 of the factor I gene. Based on the test results predicting the functional effects, this change was proposed as benign, although complete functional studies are needed to rule out its association with this disease. Based on these results and confirming that the patient did not meet (at the time of the diagnosis) the recommended requirements for taking eculizumab, treatment was started with an angiotensin-converting enzyme inhibitor at the maximum tolerated dosage, reducing proteinuria by approximately 40% from its maximum value of 6 g/day and maintaining normal renal function until now. In the event of renal function deterioration and/or increase in proteinuria despite renin---angiotensin---aldosterone system blockade, the experts recommended starting treatment with eculizumab or immunosuppressive therapy with mycophenolate mofetil if eculizumab is not available or if the patient does not clearly meet the criteria for eculizumab.
Conflicts of interest The authors declare that they have no conflicts of interest.
References Prognosis The accumulated experience indicates that the long-term prognosis is poor, given that a high percentage of patients progress to ESRD (approximately 50% of patients with DDD and 15---20% with GNC3 at 10 years), which might be due to the lesser aggressiveness of GNC3.1,19---24,31,32,38,39,41,44---46 A possible explanation is the increased prevalence of C3 nephritic factor in DDD (80% vs. 45---50% in GNC3). It is clear that more studies and case series are needed to assess the long-term prognosis of this new entity.
Conclusions and recommendations C3 glomerulopathy is a rare condition with an unfortunate renal prognosis, whose diagnosis is based on the finding of isolated C3 deposits in the renal biopsy. The detection of low
1. Servais A, Fremeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann J, et al. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J Med Genet. 2007;44:193---9. 2. Fakhouri F, Fremeaux-Bacchi V, Noel L-H, Cook HT, Pickering MC. C3 glomerulopathy: a new classification. Nat Rev Nephrol. 2010;6:494---9. 3. Appel GB, Cook HT, Hageman G, Jennette JC, Kashgarian M, Kirschfink M, et al. Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol. 2005;16:1392---403. 4. Lachmann PJ. The amplification loop of the complement pathways. Adv Immunol. 2009;104:115---49. 5. Nasr SH, Valeri AM, Appel GB, Sherwinter J, Stokes MB, Said SM, et al. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol. 2009;4: 22---32.
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8 6. Smith RJH, Alexander J, Barlow PN, Botto M, Cassavant TL, Cook HT, et al. Dense Deposit Disease Focus Group: new approaches to the treatment of dense deposit disease. J Am Soc Nephrol. 2007;18:2447---56. 7. Sethi S, Fervenza FC, Zhang Y, Nasr SH, Leung N, Vrana J, et al. Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement. J Am Soc Nephrol. 2011;6:1009---17. 8. Alpers CE, Smith KD. Cryoglobulinemia and renal disease. Curr Opin Nephrol Hypertens. 2008;17:243---9. 9. Trendelenburg M, Fossati-Jimack L, Cortes-Hernandez J, Turnberg D, Lewis M, Izui S, et al. The role of complement in cryoglobulin-induced immune complex glomerulonephritis. J Immunol. 2005;175:6909---14. 10. Yamabe H, Johnson RJ, Gretch DR, Fukushi K, Osawa H, Miyata M, et al. Hepatitis C virus infection and membranoproliferative glomerulonephritis in Japan. J Am Soc Nephrol. 1995;6: 220---3. 11. Smith RJH, Alexander J, Barlow PN, Botto M, Cassavant TL, Cook HT, et al. New approaches to the treatment of dense deposit disease. J Am Soc Nephrol. 2007;18:2447---56. 12. Cameron JS, Turner DR, Heaton J, Williams DG, Ogg CS, Chantler C, et al. Idiopathic mesangiocapillary glomerulonephritis: comparison of types I and II in children and adults and long-term prognosis. Am J Med. 1983;74:175---92. 13. West CD. Idiopathic membranoproliferative glomerulonephritis in childhood. Pediatr Nephrol. 1992;6:96---103. 14. Carroll MC. The complement system in regulation of adaptive immunity. Nat Immunol. 2004;5:981---6. 15. Sandhu G, Bansal A, Ranade A, Jones J, Cortell S, Markowitz GS. C3 glomerulopathy masquerading as acute postinfectious glomerulonephritis. Am J Kidney Dis. 2012;60: 1039---43. 16. Levy M, Halbwachs-Mecarelli L, Gubler M-C, Kohout G, Bensenouci A, Niaudet P, et al. H deficiency in two brothers with atypical dense intramembranous deposit disease. Kidney Int. 1986;30:949---56. 17. Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, et al. Heterozygous and homozygous factor H deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol. 2004;15:787---95. 18. Licht C, Heinen S, Jozsi M, Löschmann I, Saunders RE, Perkins SJ, et al. 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. 19. Martinez-Barricarte R, Heurich M, Valdes-Canedo F, VazquezMartul E, Torreira E, Montes T, et al. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J Clin Invest. 2010;120:3702---12. 20. Sethi S, Fervenza FC, Zhang Y, Zand L, Vrana JA, Nasr SH, et al. C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and followup. Kidney Int. 2012;82: 465---73. 21. Gale DP, de Jorge EG, Cook HT, Martinez-Barricarte R, Hadjisavvas A, Adam G, et al. Complement factor H-related protein 5 (CFHR5) nephropathy: an endemic cause of renal disease in Cyprus. Lancet. 2010;376:794---801. 22. Athanasiou Y, Voskarides K, Gale DP, Damianou L, Patsias C, Zavros M, et al. Familial C3 glomerulopathy associated with CFHR5 mutations: Clinical characteristics of 91 patients in 16 pedigrees. Clin J Am Soc Nephrol. 2011;6: 1436---46. 23. Servais A, Noel LH, Roumenina LT, le Quintrec M, Ngo S, Dragon-Durey MA, et al. Acquired and genetic complement
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abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 2012;82:454---64. Habbig S, Mihatsch MJ, Heinen S, Beck B, Emmel M, Skerka C, et al. C3 deposition glomerulopathy due to a functional factor H defect. Kidney Int. 2009;75:1230---4. Martínez-Barricarte R, Heurich M, Valdes-Ca˜ nedo F, VazquezMartul E, Torreira E, Montes T, et al. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J Clin Invest. 2010;120:3702---12. Bomback A, Appel GB. Pathogenesis of the C3 glomerulopathies and reclassification of MPGN. Nat Rev Nephrol. 2012;8:634---42. Zhang Y, Meyer NC, Wang K, Nishimura C, Frees K, Jones M, et al. Causes of alternative pathway dysregulation in dense deposit disease. Clin J Am Soc Nephrol. 2012;7:265---74. Brenner BM, Cooper ME, de Zeeuw D, Grunfeld JP, Keane WF, Kurokawa K, et al. The losartan renal protection study----rationale, study design and baseline characteristics of RENAAL (Reduction of endpoints in NIDDM with the angiotensin II antagonist losartan). J Renin Angiotensin Aldosterone Syst. 2000;1:328---35. Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, et al. Renoprotective properties of ACE-inhibition in nondiabetic nephropathies with nonnephrotic proteinuria. Lancet. 1999;354:359---64. Schmidt CQ, Slingsby FC, Richards A, Barlow PN. Production of biologically active complement factor H in therapeutically useful quantities. Protein Expr Purif. 2011;76:254---63. McCaughan JA, O’Rourke DM, Courtney AE. Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies. Am J Transplant. 2012;12: 1046---51. Bomback AS, Smith RJ, Barile GR, Zhang Y, Heher EC, Herlitz L, et al. Eculizumab for dense deposit disease and C3 glomerulonephritis. Clin J Am Soc Nephrol. 2012;7: 748---56. Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111:1840---7. Ariceta G, Arrizabalaga B, Aguirre M, Morteruel E, LopezTrascasa M. Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants. Am J Kidney Dis. 2012;59: 707---10. Burwick RM, Feinberg BB. Eculizumab for the treatment of preeclampsia/HELLP syndrome. Placenta. 2013;34:201---3. Gianella-Borradori A, Borradori L, Schneider PM, Gautier E, Späth PJ. Combined complete C5 and partial C4 deficiency in humans: clinical consequences and complement-mediated functions in vitro. Clin Immunol Immunopathol. 1990;55:41---55. Bouts A, Monnens L, Davin JC, Struijk G, Spanjaard L. Insufficient protection by Neisseria meningitidis vaccination alone during eculizumab therapy. Pediatr Nephrol. 2011;26: 1919---20. Vivarelli M, Pasini A, Emma F. Eculizumab for the treatment of densedeposit disease. N Engl J Med. 2012;366:1163---5. Daina E, Noris M, Remuzzi G. Eculizumab in a patient with dense-deposit disease. N Engl J Med. 2012;366:1161---3. Radhakrishnan S, Lunn A, Kirschfink M, Thorner P, Hebert D, Langlois V, et al. Eculizumab and refractory membranoproliferative glomerulonephritis. N Engl J Med. 2012;366:1165---6. Gurkan S, Fyfe B, Weiss L, Xiao X, Zhang Y, Smith RJ. Eculizumab and recurrent C3 glomerulonephritis. Pediatr Nephrol. 2013;28:1975---81. Zuber J, Fakhouri F, Roumenina L, Loirat C, Frémeaux-Bacchi V. Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies. Nat Rev Nephrol. 2012;8:643---57.
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C3 glomerulopathy: A new complement-based entity 43. Rabasco-Ruiz C, Huerta-Arroyo A, Caro-Espada J, GutiérrezMartínez E, Praga-Terente M. Glomerulopatías C3. Una nueva perspectiva en enfermedades glomerulares. Nefrologia. 2013;33:164---70. 44. Darouich S, Goucha R, Jaafoura MH, Zekri S, Kheder A, Ben Maiz H. Membranoproliferative glomerulonephritis with isolated C3 deposits: case report and literature review. Ultrastruct Pathol. 2011;35:42---6.
9 45. Deltas C, Gale D, Cook T, Voskarides K, Athanasiou Y, Pierides A. C3 glomerulonephritis/CFHR5 nephropathy is an endemic disease in Cyprus: clinical and molecular findings in 21 families. Adv Exp Med Biol. 2013;735:189---96. 46. Sugimoto K, Fujita S, Miyazaki K, Okada M, Takemura T. C3 glomerulonephritis associated with a missense mutation in the factor H gene. Tohoku J Exp Med. 2012;227: 211---5.
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Rev Clin Esp. 2014;xxx(xx):xxx---xxx
Revista Clínica Española www.elsevier.es/rce
CLINICAL UP-DATE
C3 glomerulopathy: A new complement-based entity夽 A. de Lorenzo ∗ , S. Tallón, B. Hernández-Sevillano, G. de Arriba Servicio de Nefrología, Hospital Universitario de Guadalajara, Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain Received 24 June 2013; accepted 20 January 2014
KEYWORDS C3 glomerulopathy; Dense-deposit disease; Alternative complement pathway; Factor H; Factor I; C3 nephritic factor; Eculizumab
Abstract C3 glomerulopathy is a new, recently described entity that has changed the perspective, treatment and classification of a number of glomerular diseases. It encompasses 2 similar but clearly differentiated pathologies----the dense-deposit disease and C3 glomerulonephritis itself. The alternative complement pathway plays a fundamental role in its pathogenesis and, specifically, the mutations and defects in its regulatory factors (mainly factor H and factor I), as well as the presence of acquired autoantibodies (C3 nephritic factor), which generates an unbridled activation of the system, and ultimately, a deposit of its products at the glomerular level. Its poor prognosis and onset in young populations make the detailed study of new therapeutic alternatives for this disease essential. Recently eculizumab, an anti-C5 antibody, has demonstrated effectiveness in the treatment of these patients. © 2013 Elsevier Espa˜ na, S.L. All rights reserved.
PALABRAS CLAVE
Glomerulopatía C3: una nueva entidad basada en el complemento
Glomerulopatía C3; Enfermedad por depósitos densos; Vía alternativa del complemento; Factor H; Factor I; Factor nefrítico C3; Eculizumab
Resumen La glomerulopatía C3 es una nueva entidad descrita recientemente que ha cambiado la visión, el tratamiento y la clasificación de algunas enfermedades glomerulares. Engloba 2 patologías similares pero claramente diferenciadas: la enfermedad por depósitos densos y la glomerulonefritis C3 propiamente dicha. La vía alternativa del complemento juega un papel fundamental en su patogenia, y en concreto las mutaciones o defectos en sus factores reguladores (fundamentalmente factor H y factor I), así como la presencia de autoanticuerpos adquiridos (factor nefrítico C3) que generan una activación desenfrenada del sistema, y en último término un depósito de sus productos a nivel glomerular. Su mal pronóstico y la aparición en población joven hacen preciso el estudio de nuevas alternativas terapéuticas. Recientemente eculizumab, un anticuerpo anti C5, ha demostrado efectividad en el tratamiento de estos pacientes. © 2013 Elsevier Espa˜ na, S.L. Todos los derechos reservados.
夽 Please cite this article as: de Lorenzo A, Tallón S, Hernández-Sevillano B, de Arriba G. Glomerulopatía C3: una nueva entidad basada en el complemento. Rev Clin Esp. 2014. http://dx.doi.org/10.1016/j.rce.2014.01.016 ∗ Corresponding author. E-mail address: [email protected] (A. de Lorenzo).
2254-8874/$ – see front matter © 2013 Elsevier Espa˜ na, S.L. All rights reserved.
RCENG-908; No. of Pages 9
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The clinical problem Advances in the understanding of alternative complement pathway abnormalities have led to the recent discovery of a new entity in the setting of glomerular diseases. This entity is known as C3 glomerulopathy.1---4 The onset of this new disease makes the classification of membranoproliferative glomerulonephritis obsolete and opens a new field of research in the setting of its treatment using new biological therapies such as the anti-C5 monoclonal antibody eculizumab.
C3 glomerulopathy The term C3 glomerulopathy includes 2 subtypes: densedeposit disease (DDD) and C3 glomerulonephritis (GNC3) itself, 2 entities that have in common the isolated deposit of complement 3 (C3) fraction, i.e., in the absence of immunoglobulins, and which, in turn, have ultrastructural differences that allow them to be differentiated. Alternative complement pathway abnormalities cause the isolated deposit of factor C3 in the mesangium and capillary wall, which is characteristic of membranoproliferative glomerulonephritis and is produced without concomitant immunoglobulin deposit.5,6 The clinical expression is a microscopic hematuria-proteinuria syndrome with a variable degree of proteinuria, which can reach the nephrotic range. If electron-dense deposits visible by electron microscope are identified, then the disease is classified as DDD. If these deposits are absent, the disease is classified as GNC3, in which case the deposits are very similar to those of glomerulonephritis mediated by immune complexes (located at the mesangial, subendothelial, subepithelial and/or intramembranous level), although without them being present.7
A. de Lorenzo et al. Table 1 New classification of membranoproliferative glomerulonephritis. Mediated by immune complexes Infections Autoimmune diseases Neoplasms Gammopathies/dysproteinemias Mediated by complement: C3 glomerulopathy Dense-deposit disease C3 glomerulonephritis Membranoproliferative glomerulonephritis mediated by immune complexes is produced by persistent antigenemia whose resulting immune complex activates the classical complement pathway. Direct immunofluorescence stainings will be positive to immunoglobulins, mainly IgG and IgM, as well as C3 and/or C1. C3 glomerulopathy is produced by dysfunction of the alternative complement pathway (mutations or autoantibodies); its direct immunofluorescence is negative for immunoglobulins but positive for complement (C3).
To confirm a suspected diagnosis, a renal biopsy is essential. Here the diagnostic criterion is the presence of electron-dense deposits in the GBM, along with direct immunofluorescence for C3 and the absence of immunoglobulin deposits in most cases, as well as a reduction in plasma C3 levels, whose levels need to be determined. Once the diagnosis has been confirmed and depending on the availability at each center, a complement study should be requested.11 Approximately 50% of affected individuals progress to end-stage renal disease (ESRD) at 10 years after diagnosis, although the course is more aggressive and rapid in young patients and women.12,13
Dense-deposit disease This is an extremely rare disease (2---3 cases per million) that mainly affects children and young adults and is slightly more common in women (3:2 ratio). Clinically, the disease presents with varying amounts of proteinuria and hematuria. The essential characteristic that defines and differentiates this entity is the presence of electron-dense deposits in the glomerular basement membrane (GBM) and mesangium, and not the presence or absence of a membranoproliferative pattern observed under optical microscopy consisting of the thickening of the GBM along with the proliferation of mesangial cells (which is only present in 25% of affected individuals). The most common histological pattern is mesangial proliferation (45%). For this reason, we can say that the term membranoproliferative glomerulonephritis (MPGN) type II has become obsolete. In fact, MPGN is currently classified as mediated by immune complexes (which include types I and III, caused most often by the hepatitis B and C viruses whose antigenemia causes the depositing of immune complexes at the glomerular level)8---10 and by the complement (DDD and GNC3) (Table 1). Given that there is a deregulation of the alternative complement pathway in the origin of DDD, 60---80% of cases have complement consumption data manifested by low serum levels of C3 and degradation products.
C3 glomerulonephritis The concept of GNC3 was coined in 2007 when Servais et al.1 described what is known as ‘‘primary glomerulonephritis with isolated C3 deposits’’. The fundamental requirement for the diagnosis of this entity, as with DDD, was the isolated deposits of C3 on immunofluorescence. It was noteworthy that these patients had none of the typical characteristics of DDD, and in fact the deposits resembled those of MPGN types I and III, with the significant exception that they lacked immune complexes. Reduced serum C3 levels appear less frequently than in DDD in 40% of cases. There are no major differences in terms of the clinical presentation between DDD and GNC3, although GNC3 has a slightly better prognosis; approximately 20% of patients progress to ESRD at 10 years, and 30% progress to stages 3---4 CKD.1
Etiopathogenesis The complement system is a mechanism mainly involved in defending against infections (mainly gram negative germs) and tumor cells. The system consists of approximately 30 factors that are mostly plasma proteins. Complement activation can be initiated by 3 different pathways (classical,
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C3 glomerulopathy: A new complement-based entity Factor H
-
C3
convertasa
+
C3
+ +
C3 nephritic factor
C3b +
Factor I
Alternative pathway
C3i
Terminal cascade
C5
convertase
C5 +
C5b
MAC Figure 1 Alternative complement pathway. In the activation of the alternative complement pathway, C3 convertase cleaves C3 into C3a and C3b, the latter of which is a potent C3 convertase amplifier and generator. This process is regulated by factor H (which inhibits C3 convertase) and factor I (which converts C3b into inactive C3b, thereby slowing the cascade). In addition, C5 convertase is generated from the products derived from the action of C3 convertase. This enzyme cleaves C5 into C5a and C5b. The binding of C5b with C6---C9 forms the membrane attack complex (MAC) with chemotactic activity in the cell surfaces, resulting in cell lysis.
alternative and lectin). It involves changes in particular components that result in chain reactions, in such a way that active products are generated that, in addition to ensuring that the chain continues to the next reaction, can have important biological activities in the body’s defense. All these are due to the fact that most complement factors are proteolytic in nature.14 The alternative complement pathway is generally active in circulation, although at low levels due to regulatory mechanisms that prevent selfharm. There are 2 main regulators of this pathway: factors H and I, whose abnormalities (either inherited or acquired) create an imbalance between activating and inhibiting factors (Fig. 1). DDD and GNC3 have a common etiopathogenic origin in the mutations of the alternative complement pathway. A disorder in the regulation of C3 and C5 convertases generates an unbridled activation of the system and a considerable quantity of C3b and membrane attack complex (MAC), which ends by accumulating in the glomerular capillary wall, ultimately generating C3 glomerulopathy.15 DDD and GNC3 can probably be differentiated by the degree to which one or the other convertase is affected. It seems that in the case of DDD, the predominant disorder is at the C3 convertase level, while the origin of GNC3 is mainly due to a C5 convertase disorder. In recent years, there have been numerous publications on this disease. Several mutations of genes involved in this process of improper activation of the complement have been reported, such as CFHR5, factor H, factor I and factor
3 C3,16---19 although the majority of patients have polymorphisms of several genes. These polymorphisms generate new epitopes that determine the development of autoantibodies known as C3 nephritic factor, which acts as a stabilizer of C3 convertase, preventing the action of physiological regulators such as factor H. Thus, for DDD, 60---80% of cases progress with complement consumption data manifested by low serum levels of C3 and products resulting from its degradation. In GNC3, the percentage of reduced C3 is somewhat lower, appearing in 40% of patients. Sethi et al.20 reported on a series of 12 patients with GNC3 and alternative complement pathway disorder. Initially, 9 of the 12 patients with GNC3 were classified as having MPGN I (n = 4), MPGN III (n = 1) and postinfectious glomerulonephritis (n = 4). The Sethi group showed that the proteomic profile of GNC3 was similar to that of DDD (with a predominance of C3 and final complement pathway components). This result supports the theory that the presence of isolated C3 is the main marker of alternative complement pathway dysfunction in C3 glomerulopathy, regardless of its optical or ultrastructural histology. The greatest contribution from the genotypic and phenotypic points of view has been the data from 2 recently published cohorts. The first, published in 2010 by Gale et al.21 describes 91 patients belonging to 16 families of Cypriot origin with a CFHR5 mutation that encodes protein 5 related to factor H. The mutation was more common in men than in women (80% vs. 21%). In this case, the condition was labeled nephropathy CFHR5, characterized by persistent microscopic hematuria with gross hematuria coinciding with intercurrent upper respiratory infection (imitating the typical presentation of nephropathy by IgA deposits), as well as proteinuria in 38% of the cases, with progression to ESRD more likely in these cases, especially for males (78% vs. 22%).22 In 2012, Servais et al.23 studied a French cohort of 85 patients with C3 glomerulopathy, 56 of them with GNC3 and 29 with DDD. Sixty percent of the patients had microscopic hematuria; the proteinuria levels were slightly lower in the cases with GNC3 than in those with DDD (3.6 ± 3.3 g vs. 5.6 ± 4.5 g). Although both conditions are present in the young population, the patients with GNC3 were older (30.3 ± 19.3 vs. 18.9 ± 17.7 years). These authors were also the first to shed light on the possible etiological origin of GNC3, given that 31% of their patients had a mutation in factor H, factor I or in the membrane cofactor protein. They also observed that C3 nephritic factor was less common in GNC3 than in DDD (45% vs. 86%), which also occurred with reduced serum C3 levels (86.4% vs. 45.3%). Habbig et al.24 reported on a family with 2 siblings of consanguineous parents with hematuria and proteinuria since childhood. Both siblings had reduced levels of serum C3 and complement regulatory factor B. A mesangial deposit of C3 and C5b-9 was observed in the biopsy, and numerous mesangial, intramembranous and subendothelial deposits were observed under electron microscopy. Genetic screening for factor H mutations showed that both children were homozygous for a lysine deletion. This deletion leads to a critical reduction of this cofactor inhibitor. Additionally, both patients and their healthy mother were positive for C3 nephritic factor. In 2010, Martínez-Barricarte et al.25
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A. de Lorenzo et al. Table 2
Case series of C3 glomerulopathy: characteristics, treatment and evolution.
Author
n
Diagnosis
Mutation
C3 nephritic factor
Native kidTreatment ney/transplant
Response/ evolution
Servais et al. (2007)1
19
GNC3
Factor H (n = 3) Factor I (n = 2) MCP (n = 1)
Positive (n = 7)
N
RAASI (n = 8) E (n = 5)
Habbig et al. (2009)24
2
GNC3
Factor H (n = 2)
Positive
N
MartínezBarricarte et al. (2010)19 Darouich et al. (2011)44 Gale et al. (2010)21 Athanasiou et al. (2011)22 Deltas et al. (2013)45 Sugimoto et al. (2012)46
3
DDD
C3
Negative
N (n = 2) T (n = 1)
Fresh plasma infusion ND
1
GNC3
ND
ND
N
ND
ND
Glom.C3
Factor H (CFHR5)
Negative (n = 4)a
N
ND
RF deterioration to ESRD (n = 28)
1
GNC3
Factor H
Negative
N
RAASI
Sethi et al. (2012)20
12
GNC3
Factor H (n = 2) Factor I (n = 1)
Positive (n = 5)
N (n = 10) T (n = 2)
Servais et al. (2012)23
85
GNC3 (n = 56)
Factor H (n = 7) Factor I (n = 3) MCP (n = 1) Factor H (n = 5)
Positive (n = 24)
N and T (number not specified)
RAASI (n = 2) RAASI + E (n = 7) MMF (n = 3) E + CFM (n = 1) RAASI (n = 19) IS (n = 19) RAASI (n = 14) IS (n = 14) Eculizumab
No RF impairment Increased Pr No RF impairment (n = 10). No response (n = 2)
136
DDD (n = 29)b
Positive (n = 19)
McCaughan et al. (2012)31 Bomback et al. (2012)32
1
DDD
No
Positive
T
6
GNC3 (n = 3) DDD (n = 3)
Factor H (n = 1) MCP (n = 1)
Positive (n = 3)
N (n = 3) T (n = 3)
Eculizumab
Vivarelli et al. (2012)38 Daina et al. (2012)39
1
DDD
No
Positive
N
Eculizumab
1
DDD
No
Positive
N
Eculizumab
Gurkan et al. (2013)41
1
GNC3
No
Positive
T
Eculizumab
RF impairment (n = 15), of these ESRDs (n = 5) No disease progression ND
RF deterioration to ESRD (n = 27) RF deterioration to ESRD (n = 23) Reduction of Cr and Pr Reduction of Cr (n = 2) and Pr (n = 1). Increase of Alb (n = 1) Reduction of Pr Increase of Alb Reduction of Cr and Pr Increase of Alb Stable Cr and Pr Histopathologic progression
Alb, plasma albumin; CFM, cyclophosphamide; Cr, plasma creatinine; E, steroids; DDD, dense-deposit disease; ESRD, end-stage renal disease; RF, renal function; Glom.C3, glomerulopathy C3; GNC3, glomerulonephritis C3; RAASI, renin---angiotensin---aldosterone system inhibitors; MMF, mycophenolate mofetil; N, native kidney; ND, not described; MCP, membrane cofactor protein; Pr, proteinuria; and T, kidney transplant. a Measurement performed in 4 patients. b The total number of patients in the series is complete with 41 patients who were diagnosed with type I membranoproliferative glomerulonephritis.
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C3 glomerulopathy: A new complement-based entity
5 Renal biopsy Diverse glomerular histology with/without MPGN pattern
Mesangial proliferation with duplication of the GBM (MPGN pattern)
IF Immunoglobulins with/without C3
Isolated C3
Autoimmune diseases Mediated by immune complexes + classical complement pathway
Infections
Mediated by alternative complement pathway
Gammopathies Dysproteinemias
Electron M. deposits
Mesangial and subendothelial
MPGN type I
Mesangial, subendothelial, subepithelial and/or intramembranous
MPGN type III
Electron M. deposits
Mesangial, subendothelial, subepithelial and/or intramembranous
Mesangial and intramembranous
GNC3
DDD
Figure 2 Classification of membranoproliferative glomerulonephritis. Abbreviations: DDD, dense-deposit disease; GNC3, C3 glomerulonephritis; MPGN, membranoproliferative glomerulonephritis; IF, immunofluorescence; electron M., electron microscope; and GBM, glomerular basement membrane.
published a report on a family with DDD and a C3 mutation. This mutation conferred resistance to C3 against its excision by C3 convertase, thereby preventing the formation of activated C3b. The disease in this family was caused exclusively by dysregulation in the fluid phase of the alternative pathway with no contribution from the terminal complement cascade (TCC). In contrast, the GNC3 described in the Cypriot families by Gale et al.21 and in the siblings by Habbig et al. were associated with the C5 convertase disorder and the subsequent activation of the TCC (Table 2). The alternative complement pathway disorder could also be due to acquired causes that trigger the formation of 2 types of antibodies (Ab), various inhibitors (antifactor H Ab and antifactor I Ab) and others that directly stimulate complement activation such as C3 nephritic factor, an IgG autoantibody that stabilizes C3 convertase, extending its half-life and enzymatic activity.
in relatives with subclinical involvement. Experts recommend measuring serum levels of CH50, C3, C3d, C4, factor H and factor I, studying their mutations, assessing the presence of autoantibodies such as C3 nephritic factor and conducting functional trials of the alternative complement pathway (Fig. 2).20,26,27
Treatment Despite significant progress in the understanding of the underlying mechanisms, advances in treatment have not enabled the development of effective compounds. Various treatment modalities are used with varying degrees of effectiveness. Examples of treatments include renin---angiotensin axis blockade, plasmapheresis with plasma infusion and cellular immunosuppressants. The exception to this rule is biological therapy directed using the anti-C5 monoclonal antibody eculizumab.
Assessment of patients with C3 glomerulopathy
Renin---angiotensin axis inhibitors
In the clinical assessment of patients with C3 glomerulopathy, the identification of the underlying defect in the alternative complement pathway can be very useful. It allows a family study to be carried out and prevents damage
The current evidence on chronic kidney disease and glomerulopathy with nonselective proteinuria, as well as the data obtained by Servais et al.23 in this group of diseases, support the use of angiotensin-converting enzyme inhibitors
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Plasma therapy
Maintenance
Experience with its use is based on individual cases, such as the report by Lich et al.18 of 2 twins diagnosed with DDD and the previously mentioned report by Habbig et al.24 Both cases had factor H deficiency secondary to a mutation and a satisfactory response to factor H repletion achieved using plasma exchange. The direct contribution of this factor could be available for therapeutic use in the near future.30 In other cases, plasmapheresis with replenishment of plasma factors has not been effective, according to the reports by McCaughan et al.31 and Martinez-Barricarte et al.,25 all of which dealt with DDD. Martinez-Barricarte et al. postulated the presence of a C3 convertase mutation that would make it resistant to the inhibitory action of factor H and would therefore hinder the effectiveness of replenishing plasma factor. This would in turn require new specific treatments aimed at restoring control of C3 convertase activity and eliminating C3 degradation products from plasma.20
1200 mg every 2 weeks 900 mg every 2 weeks 600 mg every 2 weeks 300 mg every 2 weeks 300 mg every 2 weeks
Administrationa
(ACEI) and angiotensin II receptor antagonists (ARA II) to preserve renal function in this group of diseases.28,29
240 mL in 30---45 min 180 mL in 30---45 min 120 mL in 30---45 min 60 mL in 30---45 min 60 mL in 30---45 min
6
Administrationa
There is no evidence supporting the use of immunosuppressive therapy in C3 glomerulopathy,3 given that the various lines of treatment have provided highly variable responses and questionable efficacy, as is the case with prednisone and mycophenolate, which have shown no benefit according to the cases reported by Sethi et al.20 and Bomback et al.32 The combination of these agents with biological therapies, such as the antilymphocyte CD20 monoclonal antibody rituximab used by McCaughan et al.,31 was also ineffective in a kidney transplant recipient.
180 mL in 30---45 min 120 mL in 30---45 min 120 mL in 30---45 min 120 mL in 30---45 min 60 mL in 30---45 min
Cellular immunosuppression
Induction
900 mg/week; 4 dose 600 mg/week; 2 dose 600 mg/week; 2 dose 600 mg single dose 300 mg single dose
Weight
>40 kg 30---40 kg 20---30 kg 10---20 kg 5---10 kg
Table 3
Eculizumab is an anti-C5 antibody that impedes the excision of C5 in C5b and decreases the production of C5a, thereby preventing the activation of the terminal cascade and the formation of CAM (Table 3).7 Eculizumab was the first drug that, using this mechanism of action, managed to effectively and safely reduce hemolysis in paroxysmal nocturnal hemoglobinuria. This condition was the first indication for eculizumab in 2008,33 although practically every year new applications and therapeutic indications are being discovered for numerous diseases mediated by the complement, such as atypical hemolytic-uremic syndrome,34 C3 glomerulopathy and HELLP syndrome.35 The most important secondary effect of eculizumab is a direct consequence of the inhibition of the terminal complement cascade, which predisposes patients to infections by encapsulated germs such as Neisseria meningitidis. Vaccinations and antibiotic prophylaxis are therefore recommended at least 14 days before starting treatment with eculizumab.36,37 The first published cases of glomerulonephritis treated with eculizumab31,32,38---41 appeared in the literature in 2012, 6 of them with DDD, 3 with GNC3 and another diagnosed with MPGN I refractory to treatment. Of the 10 patients who
Eculizumab: dosage and method of administration.
Eculizumab
Standard dosage for patients older than 18 years: 900 mg weekly for the first 4 weeks, followed by 1200 mg on the fifth week and subsequent maintenance with 1200 mg every 2 weeks. a 300 mg vials (30 mL) in dilution 5 mg/mL with physiological saline (0.9%, 0.45%) or glucose solution (5%).
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C3 glomerulopathy: A new complement-based entity
7
C3 glomerulopathy confirmed by biopsy
Measurement of C3 nephritic factor
+
Serum levels of CH50, C3, C3d, C4, factor H, factor I
Study of factor H and factor I mutations
-
No
Yes
Treatment
Plasmapheresis plasma infusion rituximab
Plasma infusion ACEI ARA II
Eculizumab
Figure 3 Treatment. Treatment regimen based on the findings of the complement functionality and genetics study. Abbreviations: ARA II, angiotensin II receptor antagonists; and ACEI, angiotensin-converting enzyme inhibitors.
underwent the treatment, improved renal function parameters were observed in 8, with 1 patient showing lower glomerulonephritis activity at the histopathological level in a second biopsy. The 2 remaining patients experienced renal function deterioration during the follow-up, 1 of whom eventually required dialysis. It is worth noting that 2 of the patients who responded positively worsened immediately after the use of eculizumab was withdrawn. An association was found between MAC levels prior to treatment and the response to the same; these levels could therefore be useful as a predictive factor. Given the high cost of therapy with this antibody, patient candidates for undergoing this therapy should be selected carefully. A recent review by Zuber et al.42 on the use of eculizumab in atypical hemolytic-uremic syndrome and C3 glomerulopathy suggested that optimal candidates for taking eculizumab would be patients with a recent diagnosis, active inflammatory lesions (crescent formation and endocapillary proliferation) and minimal interstitial fibrosis in the pathology, as well as an increase in serum creatinine and/or proteinuria levels and high serum MAC levels (Fig. 3).32,43
plasma levels of complement regulation factors can provide a criterion for selecting the optimal treatment. The rarity of the disease has precluded the availability of strong evidence, and there are only small series of patients in whom different treatment modalities have been employed. Anticomplement therapy with eculizumab has offered the most promising results so far, although it requires a careful selection of candidates, such as those without no chronicity data in the renal biopsy and with renal function impairment and/or proteinuria, as well as high levels of MAC (when their measurement is possible), because they are associated with a better treatment response. In the case of our patient, electron microscopy of the renal biopsy confirmed the diagnosis of C3 glomerulonephritis. A study was performed of the alternative complement pathway, which showed normal levels of factors I and H, with no abnormal bands in the structural characterization of factor H and the absence of antifactor H antibodies and C3 nephritic factor. The genetic study, however, detected a change in heterozygosity in exon 4 of the factor I gene. Based on the test results predicting the functional effects, this change was proposed as benign, although complete functional studies are needed to rule out its association with this disease. Based on these results and confirming that the patient did not meet (at the time of the diagnosis) the recommended requirements for taking eculizumab, treatment was started with an angiotensin-converting enzyme inhibitor at the maximum tolerated dosage, reducing proteinuria by approximately 40% from its maximum value of 6 g/day and maintaining normal renal function until now. In the event of renal function deterioration and/or increase in proteinuria despite renin---angiotensin---aldosterone system blockade, the experts recommended starting treatment with eculizumab or immunosuppressive therapy with mycophenolate mofetil if eculizumab is not available or if the patient does not clearly meet the criteria for eculizumab.
Conflicts of interest The authors declare that they have no conflicts of interest.
References Prognosis The accumulated experience indicates that the long-term prognosis is poor, given that a high percentage of patients progress to ESRD (approximately 50% of patients with DDD and 15---20% with GNC3 at 10 years), which might be due to the lesser aggressiveness of GNC3.1,19---24,31,32,38,39,41,44---46 A possible explanation is the increased prevalence of C3 nephritic factor in DDD (80% vs. 45---50% in GNC3). It is clear that more studies and case series are needed to assess the long-term prognosis of this new entity.
Conclusions and recommendations C3 glomerulopathy is a rare condition with an unfortunate renal prognosis, whose diagnosis is based on the finding of isolated C3 deposits in the renal biopsy. The detection of low
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