C3 Nephritic Factor Research Articles

Poor allograft outcome in Indian patients with post-transplant C3 glomerulopathy.

BackgroundComplement 3 glomerulopathy (C3G) results from dysfunction of the alternative complement pathway (ACP). No data are available on post-transplant C3G in South Asia.MethodsIn this study, renal allograft biopsies of C3G patients performed from 2012 to 2017 were analysed for ACP functional assay (APFA), serum complement levels, complement factor H (CFH), complement factor B (CFB) and autoantibodies to CFH and CFB. Limited genetic screening for CFH/CFHR5 genes was carried out. All study patients were also followed up.ResultsA total of 21 cases of C3G were included, of which 11 had native C3G disease (that is, recurrent C3G). Of these 11 recurrent cases, 7 presented with allograft dysfunction and 4 with proteinuria and renal dysfunction. Early post-transplant recurrence (<1 month) was noted in six patients, whereas recurrence in five patients occurred within 8–17 months of transplant. Biopsies showed mild focal mesangial expansion with or without endocapillary proliferation and thrombotic microangiopathy. Rejection was also noted in six patients. APFA/C3 levels were low in all cases. Serum CFH levels were low [dense deposit disease (DDD), 44%; C3 glomerulonephritis (C3GN), 25%], whereas CFB levels were normal. Autoantibodies to CFH, CFB and C3 nephritic factor were present in 11, 0 and 44% of DDD cases, respectively, and in 17, 17 and 33% of C3GN cases, respectively. Genetic analysis revealed only non-pathogenic CFH gene variants (93%). No novel mutation was found. At follow-up (140 months), stable graft was noted in 28% of cases, progressive renal failure in 19%, graft loss in 34%, and 19% of patients died.ConclusionPost-transplant C3G can present with graft dysfunction and/or proteinuria. Subtle histological findings demand careful interpretation of immunofluorescence results. Autoantibodies to complement pathway regulatory proteins are common, and no novel mutation has been found from limited genetic workup. Clinical outcome is poor.

Validation of distinct pathogenic patterns in a cohort of membranoproliferative glomerulonephritis patients by cluster analysis.

BackgroundA novel data-driven cluster analysis identified distinct pathogenic patterns in C3-glomerulopathies and immune complex-mediated membranoproliferative glomerulonephritis. Our aim was to replicate these observations in an independent cohort and elucidate disease pathophysiology with detailed analysis of functional complement markers.MethodsA total of 92 patients with clinical, histological, complement and genetic data were involved in the study, and hierarchical cluster analysis was done by Ward method, where four clusters were generated.ResultsHigh levels of sC5b-9 (soluble membrane attack complex), low serum C3 levels and young age at onset (13 years) were characteristic for Cluster 1 with a high prevalence of likely pathogenic variations (LPVs) and C3 nephritic factor, whereas for Cluster 2—which is not reliable because of the small number of cases—strong immunoglobulin G staining, low C3 levels and high prevalence of nephritic syndrome at disease onset were observed. Low plasma sC5b-9 levels, decreased C3 levels and high prevalence of LPV and sclerotic glomeruli were present in Cluster 3, and patients with late onset of the disease (median: 39.5 years) and near-normal C3 levels in Cluster 4. A significant difference was observed in the incidence of end-stage renal disease during follow-up between the different clusters. Patients in Clusters 3–4 had worse renal survival than patients in Clusters 1–2.ConclusionsOur results confirm the main findings of the original cluster analysis and indicate that the observed, distinct pathogenic patterns are replicated in our cohort. Further investigations are necessary to analyse the distinct biological and pathogenic processes in these patient groups.

Nephritic Factors: An Overview of Classification, Diagnostic Tools and Clinical Associations.

Nephritic factors comprise a heterogeneous group of autoantibodies against neoepitopes generated in the C3 and C5 convertases of the complement system, causing its dysregulation. Classification of these autoantibodies can be clustered according to their stabilization of different convertases either from the classical or alternative pathway. The first nephritic factor described with the capacity to stabilize C3 convertase of the alternative pathway was C3 nephritic factor (C3NeF). Another nephritic factor has been characterized by the ability to stabilize C5 convertase of the alternative pathway (C5NeF). In addition, there are autoantibodies against assembled C3/C5 convertase of the classical and lectin pathways (C4NeF). These autoantibodies have been mainly associated with kidney diseases, like C3 glomerulopathy and immune complex-associated-membranoproliferative glomerulonephritis. Other clinical situations where these autoantibodies have been observed include infections and autoimmune disorders such as systemic lupus erythematosus and acquired partial lipodystrophy. C3 hypocomplementemia is a common finding in all patients with nephritic factors. The methods to measure nephritic factors are not standardized, technically complex, and lack of an appropriate quality control. This review will be focused in the description of the mechanism of action of the three known nephritic factors (C3NeF, C4NeF, and C5NeF), and their association with human diseases. Moreover, we present an overview regarding the diagnostic tools for its detection, and the main therapeutic approach for the patients with nephritic factors.

A case of bilateral Parry-Romberg syndrome successfully treated with hyaluronic acid filler augmentation.

Parry-Romberg syndrome is a rare acquired neurocutaneous disorder typically characterized by hemifacial atrophy. Few cases of bilateral facial involvement have been reported. We report a case of a 60-year-old female with a 20-year history of progressive bilateral facial atrophy. Although an initial diagnosis of acquired partial lipodystrophy was considered, a diagnosis of bilateral Parry-Romberg was favored for three main reasons: (a) lipoatrophy was confined to the face (b) imaging findings of enophthalmos and underlying white matter changes (c) laboratories showing absence of C3 nephritic factor and normal complement levels. The patient was treated with hyaluronic acid fillers with dramatic improvement in cosmetic appearance.

Utility of plasma exchange in early recurrent C3 glomerulopathy

Introduction: Treatment options for recurrent C3 glomerulopathy (C3G) are not explored in large trials. Only Eculizumab has been successfully used to improve the renal function in patients with recurrent C3G. In the current report, we are sharing our experience with plasma exchange (PLEX) in the management of early recurrent C3G post-renal transplantation. Materials and Methods: A total of four patients underwent PLEX. Time to recur was less than two weeks in all the patients. Serology levels, autoantibody testing and limited genetic workup was done in all the four patients. The clinical details of patients were recorded. Results: All the patients underwent 5 PLEX (40 ml/kg/session) with fresh frozen plasma as the replacement. The median time for post-transplant recurrence was 3-days. Immediate reduction in serum creatinine was seen in three (75%) patients. After a median last follow-up of 8.5 (range: 4-18) months, two (50%) patients achieved remission and the other two (50%) had resistant disease resulting in graft loss. Three patients tested positive for autoantibodies (two cases had positive C3-nephritic factor and one had anti-complement factor-H autoantibodies. Complement factor H gene analysis revealed rs1061170; p.His402Tyr (missense variant), rs1061147; p.Ala307= (synonymous variant) and rs2274700; p.Ala473= (synonymous variant) in three cases. All the three patients who had immediate response to PLEX had positive autoantibodies against complement pathway regulators. Conclusion: In the present report, we performed extensive workup for complement pathway abnormality and found that patients with recurrent C3G following transplantation having autoantibodies benefited with PLEX.

Both Monoclonal and Polyclonal Immunoglobulin Contingents Mediate Complement Activation in Monoclonal Gammopathy Associated-C3 Glomerulopathy.

C3 glomerulopathy (C3G) results from acquired or genetic abnormalities in the complement alternative pathway (AP). C3G with monoclonal immunoglobulin (MIg-C3G) was recently included in the spectrum of “monoclonal gammopathy of renal significance.” However, mechanisms of complement dysregulation in MIg-C3G are not described and the pathogenic effect of the monoclonal immunoglobulin is not understood. The purpose of this study was to investigate the mechanisms of complement dysregulation in a cohort of 41 patients with MIg-C3G. Low C3 level and elevated sC5b-9, both biomarkers of C3 and C5 convertase activation, were present in 44 and 78% of patients, respectively. Rare pathogenic variants were identified in 2/28 (7%) tested patients suggesting that the disease is acquired in a large majority of patients. Anti-complement auto-antibodies were found in 20/41 (49%) patients, including anti-FH (17%), anti-CR1 (27%), anti-FI (5%) auto-antibodies, and C3 Nephritic Factor (7%) and were polyclonal in 77% of patients. Using cofactor assay, the regulation of the AP was altered in presence of purified IgG from 3/9 and 4/7 patients with anti-FH or anti-CR1 antibodies respectively. By using fluid and solid phase AP activation, we showed that total purified IgG of 22/34 (65%) MIg-C3G patients were able to enhance C3 convertase activity. In five documented cases, we showed that the C3 convertase enhancement was mostly due to the monoclonal immunoglobulin, thus paving the way for a new mechanism of complement dysregulation in C3G. All together the results highlight the contribution of both polyclonal and monoclonal Ig in MIg-C3G. They provide direct insights to treatment approaches and opened up a potential way to a personalized therapeutic strategy based on chemotherapy adapted to the B cell clone or immunosuppressive therapy.

Functional characterization of disease-associated variants of human factor H-related protein 5

The alternative pathway of complement is implicated in the pathogenesis of several renal diseases, such as atypical hemolytic uremic syndrome, dense deposit disease and other forms of C3 glomerulopathy. The underlying complement defects include genetic and/or acquired factors, the latter in the form of autoantibodies. Because the autoimmune forms require a specific treatment, in part different from that of the genetic forms, it is important to detect the autoantibodies as soon as possible and understand their characteristics. In this overview, we summarize the types of anti-complement autoantibodies detected in such diseases, i.e. autoantibodies to factor H, factor I, C3b, factor B and those against the C3 convertases (C3 nephritic factor and C4 nephritic factor). We draw attention to newly described autoantibodies and their characteristics, and highlight similarities and differences in the autoimmune forms of these diseases.

Improvement of clinical immunofixation electrophoresis assay for C3 nephritic factor

Human cell differentiation molecules is a new terminology coined by the 8th International Workshop on Human Leukocyte Differentiation Antigens in 2004 to describe surface molecules associated with human cell differentiation. These molecules have been characterized in a series of international workshops studying a large number of monoclonal antibodies. The antibodies have been grouped according to their patterns of reactivity and are referred to as “clusters of differentiation (CD).”

C3 Glomerulopathy: Ten Years' Experience at Mayo Clinic

ObjectiveTo describe the clinicopathological features, complement abnormalities, triggers, treatment, and outcomes of C3 glomerulopathy. Patients and MethodsA total of 114 patients with C3 glomerulopathy seen at Mayo Clinic from January 1, 2007, through December 31, 2016, were evaluated in this study. ResultsThe mean age at diagnosis for the entire cohort was 40.4±22.3 years, with a median serum creatinine level and proteinuria value of 1.6 mg/dL (range: 0.3-14.7) (to convert to mmol/L, multiply by 0.0259) and 2605 mg/24 h (range: 233-24,165), respectively. Hematuria was present in 100 patients (87.7%). The C3 and C4 levels were low in 50 of 112 (44.6%) and 13 of 110 (11.8%) patients, respectively. A history of infection, positive autoimmune findings, and monoclonal gammopathy (MIg) were present in 33 of 114 (28.9%), 28 of 114 (24.6%), and 36 of 95 (37.9%) patients, respectively. However, 28 of 43 patients 50 years or older (65.1%) had MIg. A genetic variant in complement genes, C3 nephritic factor (C3Nef), and other autoantibodies was present in 26 of 70 (37.1%), 30 of 69 (43.5%), and 9 of 67 (13.4%) patients, respectively. Membranoproliferative and mesangial proliferative glomerulonephritis were the common patterns of injury. Patients without MIg were younger (mean age, 32.3±20.6 years), with a median serum creatinine level and proteinuria value of 1.4 mg/dL (range: 0.3-7.9) and 2450 mg/24 h (range: 250-24, 165) and with low C3 and C4 levels in 38 of 77 (49.4%) and 9 of 75 (12.0%) patients, respectively. Most patients received corticosteroids and other immunosuppressive drugs. In patients without MIg, at a median follow-up of 22.3 months (range: 0.1-201.1), the median serum creatinine level and proteinuria value were 1.4 mg/dL (range: 0.3-3.7) and 825.5 mg/24 h (range: 76-22, 603), and 7 patients (9.2%) had progression to end-stage renal disease. ConclusionC3 glomerulopathy is a heterogeneous disease entity with complex triggering events and abnormalities of the alternative pathway of complement. The disease tends to be progressive and exhibits a variable response to immunosuppressive therapy.

C3 glomerulopathy associated with monoclonal Ig is a distinct subtype

Monoclonal immunoglobulins (MIg) may play a causal role in C3 glomerulopathy (C3G) by impairing regulation of the alternative pathway of complement. Ninety-five patients with C3G were tested for MIg of which 36 were positive. Their mean age at diagnosis was 60 years and among patient 50 years and older, 65.1% had a MIg. At presentation, median serum creatinine and proteinuria were 1.9 mg/dL and 3.0 g/24 hours. Hematuria was present in 32 (88.9%) patients. Twelve (34.3%) patients had low C3 levels. C3 nephritic factor was detected in 45.8% patients; pathogenic variants in complement protein genes were rare. Hematologic evaluation revealed monoclonal gammopathy of renal significance in 26 patients, multiple myeloma in five, smoldering multiple myeloma in two, and chronic lymphocytic leukemia, lymphoma, or type I cryoglobulin each in one patient. After a median follow-up of 43.6 months, the median serum creatinine and proteinuria were 1.4 mg/dL and 0.8g/24 hours. Nine patients developed ESRD. Sixteen patients received MIg-targeted treatment, 17 patients received non-targeted treatment while three patients were managed conservatively. Of the 16 patients receiving MIg-targeted treatment, ten achieved complete/very good/partial hematologic response. Of these, seven achieved a complete/partial/stable renal response. Five patients receiving targeted treatment did not achieve hematologic response, none had a renal response. Patients receiving targeted treatment were more likely to have multiple myeloma/smoldering multiple myeloma. Patients receiving non-targeted treatment were more likely to have monoclonal gammopathy of renal significance. Thus, C3G with MIg is seen in older patients, C3 nephritic factor is the most common autoantibody detected, and MIg-targeted treatment may result in remission and stabilization of kidney function in a subset of these patients.

Patterns of Clinical Response to Eculizumab in Patients With C3 Glomerulopathy

Cases reports and small series of patients with C3 glomerulopathy have reported variable efficacy of eculizumab. Case series of C3 glomerulopathy. Pediatric and adult patients with C3 glomerulopathy treated with eculizumab between 2010 and 2016 were identified through the C3 glomerulopathy French registry database, and a questionnaire was sent to participating French pediatric and adult nephrology centers, as well as one pediatric referral center in Québec, Canada. Global or partial clinical renal response. Evolution of serum creatinine and proteinuria values. 26 patients (13 children/adolescents) were included. 22 (85%) patients had received steroids, plasma exchange, or immunosuppressive therapy before eculizumab, and 3 of them had rapid progression of their kidney disease despite treatment. At the initiation of eculizumab therapy, 11 (42%) patients had chronic kidney disease, 7 (27%) had rapidly progressive disease, and 3 (12%) required dialysis. After eculizumab treatment (median duration, 14 months), 6 (23%) patients had a global clinical response; 6 (23%), a partial clinical response; and 14 (54%), no response. Compared with those who had a partial clinical or no response, patients who had a global clinical response had lower estimated glomerular filtration rates, a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy. Age, extent of renal fibrosis, frequency of nephrotic syndrome, low serum C3 and C3 nephritic factor and elevated soluble C5b-9 concentrations, or complement gene variants did not differ between responders and nonresponders. Retrospective design without a control group, relatively small number of cases, inclusion of pediatric and adult cases. Eculizumab appears to be a potential treatment for patients with crescentic rapidly progressive C3 glomerulopathy. Its benefit in patients with non-rapidly progressing forms seems to be limited.

Establishment of a method for the detection of C4-nephritic factor

Establishment of a method for the detection of C4-nephritic factor

Changes in the complement system in membranoproliferative glomerulonephritis

To compare the clinical manifestations membranoproliferative glomerulonephritis (MPGN) in its idiopathic variant, lupus nephritis (LN), and C3 glomerulopathy (C3-GP), by comparing them with changes in the complement system. The clinic of nephrology followed up 42 patients with different types of MPGN in 2013 to 2015. The study included 35 patients divided into 3 groups: 1) 8 patients with C3-GP, 2) 13 with idiopathic MPGN; 3) 14 with Class IV LN. The investigators studied the blood and urine levels of components and markers for activation of the classical and alternative pathways (C3 and C4, С3а, C5a, CFH, CFB, and CFD) of the terminal complement complex (TCC). The detection rate of C3-GP was 19%. The patients with C3-GP were noted to have the lowest blood concentration of S3 and the highest urinary level of С3а, C5a, TCC, CFH, CFB, and CFD. C3 nephritic factor was detected in 2 patients from the C3-GP (dense deposit disease) group. Alternative complement pathway dysregulation caused by genetic or autoimmune factors plays a leading role in the pathogenesis of C3-GP.

C3 Glomerulopathy.

Recent advances in our understanding of the disease pathology of membranoproliferative glomerulonephritis has resulted in its re-classification as complement C3 glomerulopathy (C3G) and immune complex-mediated glomerulonephritis (IC-GN). The new consensus is based on its underlying pathomechanism, with a key pathogenetic role for the complement alternative pathway (AP), rather than on histomorphological characteristics. In C3G, loss of AP regulation leads to predominant glomerular C3 deposition, which distinguishes C3G from IC-GN with predominant immunoglobulin G staining. Electron microscopy further subdivides C3G into C3 glomerulonephritis and dense deposit disease depending on the presence and distribution pattern of electron-dense deposits within the glomerular filter. Mutations or autoantibodies affecting the function of AP activators or regulators, in particular the decay of the C3 convertase (C3 nephritic factor), have been detected in up to 80% of C3G patients. The natural outcome of C3G is heterogeneous, but 50% of patients progress slowly and reach end-stage renal disease within 10-15 years. The new classification not only marks significant advancement in the pathogenic understanding of this rare disease, but also opens doors towards more specific treatment with the potential for improved outcomes.

Insights into the Effects of Complement Factor H on the Assembly and Decay of the Alternative Pathway C3 Proconvertase and C3 Convertase

The activated fragment of C3 (C3b) and factor B form the C3 proconvertase (C3bB), which is cleaved by factor D to C3 convertase (C3bBb). Older studies (Conrad, D. H., Carlo, J. R., and Ruddy, S. (1978)J. Exp. Med.147, 1792-1805; Pangburn, M. K., and Müller-Eberhard, H. J. (1978)Proc. Natl. Acad. Sci. U.S.A.75, 2416-2420; Kazatchkine, M. D., Fearon, D. T., and Austen, K. F. (1979)J. Immunol.122, 75-81) indicated that the complement alternative pathway regulator factor H (FH) competes with factor B for C3b binding; however, the capability of FH to prevent C3bB assembly has not been formally investigated. Moreover, in the few published studies FH did not favor C3bB dissociation. Whether FH may affect C3bBb formation from C3bB is unknown. We set up user-friendly assays based on combined microplate/Western blotting techniques that specifically detect either C3bB or C3bBb, with the aim of investigating the effect of FH on C3bB assembly and decay and C3bBb formation and decay. We document that FH does not affect C3bB assembly, indicating that FH does not efficiently compete with factor B for C3b binding. We also found that FH does not dissociate C3bB. FH showed a strong C3bBb decay-accelerating activity, as reported previously, and also exerted an apparent inhibitory effect on C3bBb formation. The latter effect was not fully attributable to a rapid FH-mediated dissociation of C3bBb complexes, because blocking decay with properdin and C3 nephritic factor did not restore C3bBb formation. FH almost completely prevented release of the smaller cleavage subunit of FB (Ba), without modifying the amount of C3bB complexes, suggesting that FH inhibits the conversion of C3bB to C3bBb. Thus, the inhibitory effect of FH on C3bBb formation is likely the sum of inhibition of C3bB conversion to C3bBb and of C3bBb decay acceleration. Further studies are required to confirm these findings in physiological cell-based settings.

Serum properdin consumption as a biomarker of C5 convertase dysregulation in C3 glomerulopathy.

Properdin (P) stabilizes the alternative pathway (AP) convertases, being the only known positive regulator of the complement system. In addition, P is a pattern recognition molecule able to initiate directly the AP on non-self surfaces. Although P deficiencies have long been known to be associated with Neisseria infections and P is often found deposited at sites of AP activation and tissue injury, the potential role of P in the pathogenesis of complement dysregulation-associated disorders has not been studied extensively. Serum P levels were measured in 49 patients with histological and clinical evidence of C3 glomerulopathy (C3G). Patients were divided into two groups according to the presence or absence of C3 nephritic factor (C3NeF), an autoantibody that stabilizes the AP C3 convertase. The presence of this autoantibody results in a significant reduction in circulating C3 (P<0·001) and C5 levels (P<0·05), but does not alter factor B, P and sC5b-9 levels. Interestingly, in our cohort, serum P levels were low in 17 of the 32 C3NeF-negative patients. This group exhibited significant reduction of C3 (P < 0·001) and C5 (P < 0·001) and increase of sC5b-9 (P < 0·001) plasma levels compared to the control group. Also, P consumption was correlated significantly with C3 (r=0·798, P=0·0001), C5 (r=0·806, P < 0·0001), sC5b-9 (r=-0·683, P=0·043) and a higher degree of proteinuria (r=-0·862, P=0·013). These results illustrate further the heterogeneity among C3G patients and suggest that P serum levels could be a reliable clinical biomarker to identify patients with underlying surface AP C5 convertase dysregulation.

Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: one target, two diseases.

Autoantibodies targeting factor H (FH), which is a main alternative complement pathway regulatory protein, have been well characterized in atypical hemolytic uremic syndrome (aHUS) but have been less well described in association with alternative pathway-mediated glomerulopathies (GP). In this study, we studied 17 patients presenting with GP who were positive for anti-FH IgG. Clinical data were collected and biological characteristics were compared with those of patients presenting with anti-FH Ab-associated aHUS. In contrast to the aHUS patients, the GP patients had no circulating FH-containing immune complexes, and their anti-FH IgG had a weaker affinity for FH. Functional studies demonstrated that these Abs induced no perturbations in FH cell surface protection or the binding of FH to its ligand. However, anti-FH IgG samples isolated from three patients were able to affect the factor I cofactor activity of FH. Epitope mapping identified the N-terminal domain of FH as the major binding site for GP patient IgG. No homozygous deletions of the CFHR1 and CFHR3 genes, which are frequently associated with the anti-FH Ab in aHUS patients, were found in the GP patients. Finally, anti-FH Abs were frequently associated with the presence of C3 nephritic factor in child GP patients and with monoclonal gammopathy in adult GP patients, who frequently showed Ig Lchain restriction during reactivity against factor H. These data provide deeper insights into the pathophysiological differences between aHUS and GP, demonstrating heterogeneity of anti-FH IgG.

C3 Glomerulonephritis and Plasma Cell Dyscrasia: Expanding the Etiologic Spectrum

Background: C3 glomerulopathy (C3GP) including dense deposit disease (DDD) is mediated by abnormal activation of the alternative complement pathway (ACP). In children and young adults, mutations of complement or complement regulatory proteins are the major causative factors but in adults there appears to be an increased incidence of monoclonal gammopathy and it has been proposed that the paraprotein is functioning as a C3 nephritic factor or through other unknown mechanisms resulting in abnormal ACP activity. We describe five patients with C3GP and plasma cell dyscrasias including two patients with symptomatic multiple myeloma and three patients with monoclonal gammopathy of renal significance one of whom progressed to symptomatic myeloma. One patient with DDD and elevated C3 nephritic factor responded to myeloma therapy with cyclophosphamide plus bortezomib and dexamethasone while another patient seemed to rapidly worsen both times after receiving lenalidomide, a drug with potent immunomodulatory activity. In two patients, the effect of myeloma therapy was indeterminate secondary to advanced disease. Two patients with renal transplant had recurrence C3GP in the transplanted kidney at 2 months and four years, respectively. Conclusion: Adult patients with C3GP should be screened for plasma cell dyscrasias. Further studies are required to assess the value of myeloma-directed treatment and/or ACP inhibition.

The complement system and glomerular kidney diseases: Etiopathogenesis, diagnostics and treatment

The human immune system consists of the innate and the acquired immunity. The complement system is part of the innate immune response and it can be activated through one of the three pathways: the classical pathway, the alternative pathway and the lectin pathway. Complement activation forms the C3-convertase complex. The C3-convertase proteolytically cleaves the C3 component into C3a and C3b fragments. The C3b fragment binds to the C3-convertase to form the C5-convertase. The C5-convertase is an enzyme complex that cleaves the C5 component into C5a and C5b fragments. The C5b component binds to C6, C7, C8, C9 thus forming the terminal complex of the complement activation - the membrane attack complex (MAC) which is responsible for effector functions of the complement system. The serum complement is a mediator of C3 glomerulopathy (C3G), a group of diseases that includes membranoproliferative glomerulonephritis type II (MPGN II) or dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). These diseases are caused by a dysregulation of the alternative pathway of the complement activation system. The C3 nephritic factor (C3NeF) is an autoantibody to the alternative pathway C3-convertase, which can cause dysregulation of the pathway. Newly acquired knowledge has enabled therapeutic applications of a specific antibody to the C5 complement component (eculizumab). Eculizumab is a recombinant monoclonal antibody that exhibits high affinity for the complement component C5, with the aim to inhibit its cleavage and activation of the terminal complement pathway.

Remission of C3 glomerulopathy with rituximab as only immunosuppressive therapy

C3 glomerulopathy (C3GP) is a membranoproliferative glomerulonephritis without immunoglobulin deposits. Activation of the alternative pathway of the complement system is central in its pathogenesis. The presence of a C3 nephritic factor (C3Nef), or deficient factor H or I is associated with C3 GP. The treatment is not codified. Here we describe a case of a Caucasian male with a dense deposit disease (a form of C3GP) revealed by nephritic syndrome. C3Nef was present. We treated him with rituximab as the sole immunosuppressive regimen and obtained a complete remission on proteinuria. The effect was sustained at more than 2 years with only two courses of treatment and an excellent tolerance. Rituximab could be proposed as a treatment of C3GP associated with antibodies interfering with complement alternative pathway.