C3 glomerulopathy: consensus report
Authors: Matthew C. Pickering, Vivette D. D'Agati, Carla M. Nester, Richard J. Smith, Mark Haas, Gerald B. Appel, Charles E. Alpers, Ingeborg M. Bajema, Camille Bedrosian, Michael Braun, Mittie Doyle, Fadi Fakhouri, Fernando C. Fervenza, Agnes B. Fogo, Véronique Frémeaux-Bacchi, Daniel P. Gale, Elena Goicoechea de Jorge, Gene Griffin, Claire L. Harris, V. Michael Holers, Sally Johnson, Peter J. Lavin, Nicholas Medjeral-Thomas, B. Paul Morgan, Cynthia C. Nast, Laure-Hélène Noel, D. Keith Peters, Santiago Rodríguez de Córdoba, Aude Servais, Sanjeev Sethi, Wen-Chao Song, Paul Tamburini, Joshua M. Thurman, Michael Zavros, H. Terence Cook
Journal: Kidney International (2013)

C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group. C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group. C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition.1.Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (268) Google Scholar The term was introduced for three reasons: first, it was recognized that glomerular pathology associated with isolated C3 accumulation is far more heterogeneous than previously appreciated. Consequently, many lesions could not be satisfactorily placed within existing pathological descriptors based on morphology. For example, the absence of membranoproliferative changes on light microscopy in some cases precluded the use of descriptors like 'membranoproliferative glomerulonephritis (MPGN) type II' or 'MPGN type I with isolated deposits of C3'. Second, advances in our understanding of complement-mediated kidney injury have made it possible to identify the cause of renal disease through specific complement investigations. A renal biopsy report that classified a lesion as C3 glomerulopathy should prompt an investigation of the complement system. Third, the existence of a licensed complement inhibitor (eculizumab, Alexion Pharmaceuticals, Cheshire, CT) together with the many complement inhibitors in clinical development meant that it was therapeutically relevant to identify patient groups most likely to benefit from an anti-complement therapeutic approach. C3 glomerulopathy, by definition, encompassed complement-mediated renal disease, and defined a logical patient population in which to test the efficacy of complement inhibitors. C3 glomerulopathy incorporated rather than replaced existing disease entities where these terms were considered to be satisfactorily descriptive of the pathology, that is, dense deposit disease and C3 glomerulonephritis. The term C3 glomerulonephritis was coined to describe glomerular lesions in which there is glomerular accumulation of C3 with little or no immunoglobulin in the absence of the characteristic highly electron-dense transformation seen in dense deposit disease. C3 glomerulopathy also incorporates entities where the presence of a disease-associated complement mutation is causally associated with the underlying renal pathology. Examples include familial dense deposit disease with C3 mutation2.Martinez-Barricarte R. Heurich M. Valdes-Canedo F. 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: 3702-3712Crossref PubMed Scopus (174) Google Scholar and familial C3 glomerulonephritis with mutations in the CFHR genes.3.Gale D.P. de Jorge E.G. Cook H.T. et al.Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.Lancet. 2010; 376: 794-801Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar,4.Malik T.H. Lavin P.J. Goicoechea de Jorge E. et al.A hybrid CFHR3-1 gene causes familial C3 glomerulopathy.J Am Soc Nephrol. 2012; 23: 1155-1160Crossref PubMed Scopus (108) Google Scholar In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The meeting was organized by Matthew Pickering and Terry Cook, hosted at the Wellcome Trust Conference Centre, Hinxton, Cambridge, UK, and sponsored by an unconditional educational grant from Alexion Pharmaceuticals. The objectives of this working group were: (i) through expert-based discussion, to reach a consensus on the definition of C3 glomerulopathy; (ii) through expert-based discussion, to reach a consensus on the appropriate complement investigations that should be performed in these patients; (iii) through expert-based discussion, to reach a consensus on how complement therapeutics should be explored in C3 glomerulopathy; and (iv) to garner support for an International Registry of C3 Glomerulopathy. This document represents the current consensus view of the group. The last decade has seen increasing recognition of a spectrum of glomerular diseases in which the primary pathogenic process is abnormal control of complement activation, deposition, or degradation leading to deposition of fragments of C3 in glomeruli. The C3 fragments can be detected by immunohistochemistry (IHC)/immunofluorescence (IF) and are associated with electron-dense deposits on electron microscopy (EM). The C3 fragments are detected in routine IHC/IF by an antibody directed against C3c and positivity with this antibody is by convention said to show C3 localization (Figure 1). The term C3 glomerulopathy was suggested to encompass a range of conditions regardless of the light or electron microscopic appearances.1.Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (268) Google Scholar C3 glomerulopathy is distinct from atypical hemolytic uremic syndrome although both diseases are due to abnormal control of the alternative pathway. In atypical hemolytic uremic syndrome, activation of complement occurs on glomerular or microvascular endothelium causing a thrombotic microangiopathy; in most cases, no electron-dense deposits are seen on EM and glomerular C3 is not detected on IHC/IF. As the primary process that leads to glomerular C3 fragment deposition in C3 glomerulopathy is complement activation via the alternative pathway, typical cases do not show any deposition of immunoglobulin or of early components of the classical or lectin pathways, specifically C1q and C4c. Therefore, a purist approach would be to restrict the term solely to cases with C3 staining in the absence of immunoglobulins, C1q and C4c. However, as discussed below, well-substantiated cases occur where the pathogenesis and histopathological features are typical for C3 glomerulopathy but variable amounts of immunoglobulin are detected on IHC/IF. The converse situation also arises. In cases of post-infectious glomerulonephritis (PIGN), there may be isolated staining for C3 on IHC/IF, but the clinical features are consistent with a self-limiting immune complex–mediated process. Therefore, the problem in clinical practice is to distinguish those patients in whom the pathological process is C3 deposition due to abnormalities of complement control from those with another pathogenesis such as immune complex deposition. We suggest that the term C3 glomerulopathy be used to designate a disease process rather than just a set of biopsy appearances. This is, for example, analogous to systemic lupus erythematosus, immunoglobulin A (IgA) nephropathy or diabetic nephropathy in which, despite variable morphological appearances on biopsy, the pathologist can confidently reach a diagnosis based on the synthesis of light, electron microscopic, IHC/IF, and clinical features. We will now discuss the range of pathological appearances seen in C3 glomerulopathy and then make practical recommendations for terminology and future research. C3 glomerulopathy may show a range of features on light microscopy and EM. Light microscopic appearances include mesangial proliferative, membranoproliferative, and endocapillary proliferative; in each case, crescents may also be present. In rare cases, glomeruli may be normal by light microscopy. One of the most variable findings between cases is in the quality of the deposits seen in glomeruli on EM. In many cases, these have a distinctive highly electron-dense, osmiophilic appearance and this has been designated as dense deposit disease (Figure 2a). It is not known why the deposits develop this particular morphological appearance. In other cases, the deposits do not have this characteristic density. However, the meeting recognized that, although in typical cases there is generally good agreement among pathologists on a diagnosis of dense deposit disease, there may be cases where the decision to call the deposit 'dense' is not clear cut. In addition, the typical dense appearance may only be present in some segments of glomeruli (Figure 2b) and therefore diagnosis may be affected by EM sampling. In dense deposit disease, the deposits are typically found within the glomerular basement membrane, as rounded deposits in the mesangium, and, in many cases, in Bowman's capsule and tubular basement membranes. The glomerular deposits often form band-like or sausage-like shapes punctuated by skip areas of more normal-appearing glomerular basement membrane. These deposits tend to thicken and transform the lamina densa, but may also involve the subendothelial region and produce hump-shaped subepithelial deposits that resemble those seen in acute PIGN. Other than the difference in the morphology of the deposits on EM, which when well established may also lead to characteristic appearances on light microscopy, there are no other specific histopathological or clinical features that allow a distinction between cases of C3 glomerulopathy with the appearance of dense deposit disease and those without. By light microscopy, cases of dense deposit disease may show a range of appearances. In some, there is a typical membranoproliferative pattern, whereas others show predominantly mesangial proliferation. There may be prominent endocapillary proliferation, leukocyte infiltration, and/or crescents.5.Walker P.D. Ferrario F. Joh K. et al.Dense deposit disease is not a membranoproliferative glomerulonephritis.Mod Pathol. 2007; 20: 605-616Crossref PubMed Scopus (101) Google Scholar Glomerular and tubular basement membrane deposits are often visible by light microscopy with the help of trichrome and silver stains. C3 glomerulopathies in which the deposits do not fulfill the criteria for dense deposit disease have been designated as 'C3 glomerulonephritis'.6.Servais A. Noel L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar By definition, the deposits of C3 glomerulonephritis are less electron dense than those seen in classic dense deposit disease. On EM, there are a range of appearances. It appears that the changes that have been designated as MPGN type III of Strife and Anders often represent C3 glomerulonephritis. In these cases, there is a complex pattern of mesangial increase and glomerular basement membrane thickening with variable combinations of subendothelial, intramembranous, and subepithelial deposits associated with fraying of the lamina densa. In general, the glomerular basement membrane deposits of these examples of C3 glomerulonephritis tend to be less discrete, more ill-defined, more confluent, and more likely to blend with the extracellular matrix than those in dense deposit disease (Figure 2c). Other examples of C3 glomerulonephritis have more discrete subendothelial deposits resembling MPGN type I. Deposits in the mesangium tend to be rounded in appearance. It has been proposed by some pathologists that the appearances of the deposits on EM are highly suggestive of C3 glomerulonephritis and even of the underlying genetic defect, as, for example, in CFHR5 nephropathy. However, in the absence of larger unbiased studies, it remains to be seen whether these deposit characteristics are supportive of a given genetic defect or specific disease trigger. As described for dense deposit disease, C3 glomerulonephritis may exhibit large subepithelial hump-like deposits (Figure 2d), similar to those seen in PIGN. The significance of these humps and their relationship to intercurrent infections needs to be defined in larger studies. Light microscopy in C3 glomerulonephritis is variable and the glomerular morphology broadly corresponds to the features seen on EM. Some show a mesangial proliferative pattern and others show a membranoproliferative pattern. There may be variable endocapillary proliferation, leukocyte infiltration, and crescent formation. The ability to detect deposits by light microscopy varies between cases. There is some evidence that the morphological patterns may relate to pathogenesis, and to underlying genetic abnormalities, but this requires confirmation in larger studies. By definition, kidneys with C3 glomerulopathy show staining for complement C3 in glomeruli. In most laboratories, C3 is detected using an antibody to C3c, one of the physiological breakdown products of activated C3 (denoted C3b). These products are collectively known as the C3 fragments and comprise iC3b, C3c, and C3dg. These fragments can mediate distinct biological responses through their interactions with complement receptors. Consequently, it may be helpful in the future to use specific antibodies to different C3 fragments in order to determine their presence and relative location in glomeruli because these distinctions may reflect different pathophysiological mechanisms. Looking for the presence of C5b-9, as a marker of complement terminal pathway activation, might be relevant when considering therapeutic C5 inhibition. However, it is important to recognize that (1) C5b-9 may be detected in glomeruli from normal kidneys,7.Herlitz L.C. Bomback A.S. Markowitz G.S. et al.Pathology after eculizumab in dense deposit disease and C3 GN.J Am Soc Nephrol. 2012; 23: 1229-1237Crossref PubMed Scopus (131) Google Scholar and (2) glomerular and tubular basement membrane deposits of C5b-9 have been shown to persist in repeat renal biopsies of C3 glomerulonephritis and dense deposit disease performed 1 year after initiation of eculizumab therapy despite the normalization of soluble C5b-9 levels in serum.7.Herlitz L.C. Bomback A.S. Markowitz G.S. et al.Pathology after eculizumab in dense deposit disease and C3 GN.J Am Soc Nephrol. 2012; 23: 1229-1237Crossref PubMed Scopus (131) Google Scholar An important question concerns the presence of immunoglobulins in bona fide cases of C3 glomerulopathy (Figure 3). In many glomerular diseases, small amounts of immunoglobulin may become trapped in areas of sclerosis or accumulate as droplets in podocytes. In dense deposit disease, approximately one-third of patients with either mesangial proliferative (8 out of 28 cases) or acute proliferative and exudative (3 out 8 cases) subtypes had glomerular IgG staining.5.Walker P.D. Ferrario F. Joh K. et al.Dense deposit disease is not a membranoproliferative glomerulonephritis.Mod Pathol. 2007; 20: 605-616Crossref PubMed Scopus (101) Google Scholar Dr D'Agati and colleagues further explored the effect of applying different 'cutoff' levels of immunoglobulin deposition to cases with typical appearance of dense deposit disease on EM.8.Hou J. Markowitz G.S. Herlitz L.C. et al.Toward a working definition of C3 Glomerulopathy by immunofluorescence.Kidney Int. 2013https://doi.org/10.1038/ki.2013.340Google Scholar In summary, their data showed that only 41% of cases had C3 only (without immunoglobulin), 59% had dominant C3 with up to 1+ IgM, and 80% of cases had dominant C3 of ≥2 orders of magnitude of intensity by IF greater than any other immune reactant (using a scale of 0 to 3, including 0, trace, 1+, 2+, 3+). However, even with this liberal interpretation of dominant C3, 20% of cases of dense deposit disease would not be classified as C3 glomerulopathy. It is likely that IgM staining has a different significance from staining with IgG or IgA and this should be a subject of further study. Thus, if criteria exclude cases with any immunoglobulin deposition, it is very likely that cases in which the pathogenesis is alternative pathway dysregulation will be overlooked. Some pathologists believe that there are characteristic electron microscopic appearances in non-dense deposit disease C3 glomerulopathy. These ultrastructural findings would support the diagnosis of C3 glomerulonephritis even when immunoglobulin is present, but this requires confirmation in further studies. It is noteworthy that in a large series of cases classified as idiopathic MPGN type I on the basis of the presence of immunoglobulin in addition to complement, there was a significant incidence of either C3NeF or of genetic mutations of proteins involved in the alternative pathway.6.Servais A. Noel L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar There may be several explanations for this. First, it may be that there is an interaction between immune complex deposition and complement dysregulation; it is plausible that in some cases immune complex deposition may trigger or exacerbate disease when there is genetic or acquired complement dysregulation.1.Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (268) Google Scholar Theoretically, an initial trigger of the classical pathway might uncover a defect in the alternative pathway and then continued complement activation is sustained through the alternative pathway. This could result in an otherwise typically self-limiting illness, for example, post-infectious nephritis, entering a chronic phase. Second, it is important to remember that immunoglobulin may be seen nonspecifically in areas of scarring or in podocyte droplets. These possibilities require further study. It is not uncommon for typical cases of PIGN, particularly those beyond the acute stage, to show deposition of C3 without immunoglobulin.9.Sethi S. Fervenza F.C. Zhang Y. et al.Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement.Kidney Int. 2012; 83: 293-299Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar In this case, distinction from C3 glomerulopathy will depend on the absence of atypical features on light microscopy and EM, and also on a typical clinical course with resolution. However, it is clear that C3 glomerulopathy may present following an infectious episode, often a streptococcal infection, and, as noted above, subepithelial humps are often a feature of C3 glomerulopathy. Therefore, the presence of any atypical clinical or histological features in a case of apparent PIGN should raise suspicion of C3 glomerulopathy. More information is required on the relationship of morphological changes in biopsies with clinical features, clinical course, and outcome. Specific questions include:•What features on biopsy are best predictive of clinical course?•Are there correlations between biopsy appearances and underlying pathogenic processes particularly specific genetic mutations?•Are there characteristic electron microscopic features that are suggestive of C3 glomerulonephritis?•Which C3 fragments are deposited in glomeruli in C3 glomerulopathy and is there any significance to their relative locations? Are these C3 fragments different from those seen in either 'MPGN type I with immunoglobulin deposits' or those seen in typical post-infectious GN?•What is the etiologic and clinical significance of subepithelial hump-shaped deposits in cases of C3 glomerulopathy?•How can we refine the diagnosis of C3 glomerulopathy to deal with those cases that also have immunoglobulin deposits •The term C3 glomerulopathy should be used to designate a disease process due to abnormal control of complement activation, deposition, or degradation and characterized by predominant glomerular C3 fragment deposition with electron-dense deposits on EM.•The level of suspicion on a renal biopsy for the disease process of C3 glomerulopathy will depend on the interpretation of light microscopy, IHC, EM, and clinical history.•It is suggested that in renal biopsy diagnosis the use of the descriptive morphological term 'glomerulonephritis with dominant C3' is useful to indicate the likelihood that the case represents the disease process of C3 glomerulopathy (Figure 4).•We suggest that in practice 'glomerulonephritis with dominant C3' should be used as a morphological term for those cases with dominant staining for C3c. Dominant is defined as C3c intensity≥2 orders of magnitude more than any other immune reactant on a scale of 0 to 3 (including 0, trace, 1+, 2+, 3+).•We believe that the use of 'glomerulonephritis with dominant C3' in this way will identify most cases of C3 glomerulopathy and exclude most cases of immune complex disease, but attention must also be paid to the other histological features and clinical history. In particular, there may be EM appearances that are also very helpful in making a diagnosis of C3 glomerulopathy—particularly, the presence of features of dense deposit disease. As discussed above, some cases of typical PIGN may show C3 dominance on IHC/IF.•As with all biopsies, interpretation of individual cases depends on integration of information from the biopsy together with clinical, serological, and genetic features and, at present, no single algorithm can correctly identify all cases of C3 glomerulopathy. The role of the pathologist must be to draw attention to cases in which there is likely to be an underlying defect in the complement system.•We suggest that the term dense deposit disease be applied to those cases of C3 glomerulopathy in which characteristic very dense osmiophilic deposits are present and that other cases should be called C3 glomerulonephritis. However, we recognize that there will be borderline cases. Although the presence of dense deposit disease may be strongly suspected on the basis of light microscopy, the gold standard for diagnosis is EM.•It should be emphasized that in many cases of glomerulonephritis with subepithelial humps on EM and isolated or dominant C3 deposits, including some formerly classified as persistent or resolving PIGN and even some with a documented infection history, the differentiation of true PIGN from C3 glomerulonephritis often cannot be made on the basis of morphology and clinical and laboratory data available at the time of biopsy. According to our recommendation, a PIGN patient's biopsy may be read as 'glomerulonephritis with dominant C3 (infection-associated)'. However, this does not mean that the patient has C3 glomerulopathy. In these cases, refining the differential diagnosis will require following the patient clinically and serologically over several months to determine the course of urinary abnormalities and serum C3 levels. If these parameters do not follow a typical course of PIGN (i.e., normalization of the decreased peripheral C3 level in 8–12 weeks), a diagnosis of C3 glomerulopathy should be reconsidered and additional investigations performed as outlined below. Genetic factors have been reported in cohorts of patients with dense deposit disease, C3 glomerulonephritis, and MPGN type 1. These include, but are not limited to, mutations in the complement regulatory protein factor H, factor I, and CD46 (also termed membrane cofactor protein).6.Servais A. Noel L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar In a series of 134 patients with idiopathic MPGN type I (n=48), dense deposit disease (n=29), or C3 glomerulonephritis (n=56), mutation screening of the CFH, CFI, and CD46 genes (encoding factor H, factor I, and CD46, respectively) was performed. Out of the 134 patients screened, 17 (12.7%), 6 (4.5%), and 1 (0.7%) had mutations in the CFH, CFI, and CD46 genes, respectively.6.Servais A. Noel L.H. Roumenina L.T. et al.Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.Kidney Int. 2012; 82: 454-464Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar Conversely, 110 out of 134 (82.1%) did not have a mutation in these genes, demonstrating that in the majority of patients mutations in these genes are not present. Gain-of-function changes in the complement activation proteins, factor B10.Strobel S. Zimmering M. Papp K. et al.Anti-factor B autoantibody in dense deposit disease.Mol Immunol. 2010; 47: 1476-1483Crossref PubMed Scopus (85) Google Scholar and C3,2.Martinez-Barricarte R. Heurich M. Valdes-Canedo F. 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: 3702-3712Crossref PubMed Scopus (174) Google Scholar are rare but provide important information. For example, one gain-of-function C3 mutation associated with familial C3 glomerulopathy (reported as dense deposit disease) is resistant to inhibition by factor H.2.Martinez-Barricarte R. Heurich M. Valdes-Canedo F. 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: 3702-3712Crossref PubMed Scopus (174) Google Scholar Hence, factor H-based therapy would be predicted to be ineffective in this instance. Genomic rearrangements within the complement factor H-related genes, which do not affect the CFH gene, have been reported in familial C3 glomerulopathy. There are five complement factor H-related genes: CFHR1, CFHR2, CFHR3, CFHR4, and CFHR5. In CFHR5 nephropathy, familial C3 glomerulopathy of the C3 glomerulonephritis subtype, there is an internal duplication within the CFHR5 gene.3.Gale D.P. de Jorge E.G. Cook H.T. et al.Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.Lancet. 2010; 376: 794-801Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar This specific mutation can be screened by PCR using genomic DNA.3.Gale D.P. de Jorge E.G. Cook H.T. et al.Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.Lancet. 2010; 376: 794-801Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar In another familial C3 glomerulopathy (originally described as MPGN type III subtype), another rearrangement within the CFHR locus was detected in affected individuals. This was a hybrid CFHR3-1 gene, which can also be detected by PCR using genomic DNA.4.Malik T.H. Lavin P.J. Goicoechea de Jorge E. et al.A hybrid CFHR3-1 gene causes familial C3 glomerulopathy.J Am Soc Nephrol. 2012; 23: 1155-1160Crossref PubMed Scopus (108) Google Scholar We are aware of other rearrangements published in abstracts that include CFHR2–CFHR5 hybrid gene in familial dense deposit disease,11.Chen Q. Wiesner M. Eberhardt H. et al.A novel hybrid CFHR2/CFHR5 gene develops MPGN II and provides insights into disease mechanism and therapeutic implications.Immunobiology. 2012; 217: 1131Crossref Google Scholar an internal duplication in CFHR1 associated with dense deposit disease,12.Tortajada A. Yébenes H. Abarrategui-Garrido C. et al.C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation.J Clin Invest. 2013; 123: 2434-2446Crossref PubMed Scopus (150) Google Scholar and CFHR5 nephropathy in a family without Cypriot ancestry.13.Medjeral-Thomas N. Malik T.H. Patel M.P. et al.A novel CFHR5 fusion protein causes C3 glomerulopathy in a family without Cypriot ancestry.Kidney Int. 2013Google Scholar To detect rearrangements within the CFH-CFHR locus, copy number assays such as multiplex ligation–dependent probe assay, TaqMan qPCR, or genomic hybridization assays are needed. Outside of specifically testing for an established disease-associated variant (e.g., the internal duplication in the CFHR5 gene), complement genetic screening in these patients is de facto a candidate gene approach. It is therefore critical that the detected changes are rigorously analyzed to determine whether they represent disease-associated changes. Conditions for this could include the following: (i) the demonstration that the novel variant segregates with disease in familial cases. The lack of segregation would normally indicate that the variant is n