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• W2064717040 abstract "Whereas early classifications of membranoproliferative glomerulonephritis (MPGN) were based on morphologic features, the modern approach is directed at immunofluorescence findings. Glomerular deposits of C3 alone, without immunoglobulin, are the hallmark of alternative complement pathway dysregulation through inherited or acquired defects. These immunoglobulin-negative forms are referred to as C3 glomerulopathy, which encompasses both dense deposit disease and C3 glomerulonephritis. Distinguishing C3 glomerulopathy from immunoglobulin-mediated MPGN is opening the way to better diagnostic, prognostic, and treatment algorithms. Whereas early classifications of membranoproliferative glomerulonephritis (MPGN) were based on morphologic features, the modern approach is directed at immunofluorescence findings. Glomerular deposits of C3 alone, without immunoglobulin, are the hallmark of alternative complement pathway dysregulation through inherited or acquired defects. These immunoglobulin-negative forms are referred to as C3 glomerulopathy, which encompasses both dense deposit disease and C3 glomerulonephritis. Distinguishing C3 glomerulopathy from immunoglobulin-mediated MPGN is opening the way to better diagnostic, prognostic, and treatment algorithms. Among glomerular diseases, none has undergone greater conceptual metamorphosis over the past five years than membranoproliferative glomerulonephritis (MPGN). In the 1970s, before there was knowledge of pathogenesis, MPGN was categorized on the basis of histologic and ultrastructural findings.1.Levy M. Gubler M.C. Sich M. et al.Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (Type 1 MPGN).Clin Immunol Immunopathol. 1978; 10: 477-492Crossref PubMed Scopus (38) Google Scholar, 2.Habib R. Gubler M.C. Loirat C. et al.Dense deposit disease: a variant of membranoproliferative glomerulonephritis.Kidney Int. 1975; 7: 204-215Abstract Full Text PDF PubMed Scopus (155) Google Scholar, 3.Strife C.F. McEnery P.T. McAdams A.J. et al.Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane.Clin Nephrol. 1977; 7: 65-72PubMed Google Scholar The membranoproliferative pattern of glomerular injury is defined as mesangial interposition and duplication of glomerular basement membranes, typically associated with peripheral capillary wall immune deposits. Over the next two decades, many secondary forms with clear etiologic associations (such as related to cryoglobulinemia, dysproteinemia, autoimmune disease, and infections) were differentiated from the primary idiopathic form. But the pathologic classification of primary MPGN remained problematic because it was based largely on the ultrastructural appearance and location of deposits, devoid of pathogenetic context. Subendothelial and mesangial deposits predominated in type I MPGN, where the membranoproliferative pattern was typically well developed.1.Levy M. Gubler M.C. Sich M. et al.Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (Type 1 MPGN).Clin Immunol Immunopathol. 1978; 10: 477-492Crossref PubMed Scopus (38) Google Scholar Highly electron-dense intramembranous and mesangial deposits were the hallmark of type II, also known as dense deposit disease (DDD).2.Habib R. Gubler M.C. Loirat C. et al.Dense deposit disease: a variant of membranoproliferative glomerulonephritis.Kidney Int. 1975; 7: 204-215Abstract Full Text PDF PubMed Scopus (155) Google Scholar In type III, deposits could be subendothelial and subepithelial (Burkholder subtype) or produce complex intramembranous, subendothelial, and subepithelial formations with fraying of the lamina densa (Strife and Anders subtype).3.Strife C.F. McEnery P.T. McAdams A.J. et al.Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane.Clin Nephrol. 1977; 7: 65-72PubMed Google Scholar Even within the same biopsy or a given glomerulus, pathologists may observe overlapping features between these subtypes, defying easy classification. While hypocomplementemia was a well-recognized clinical feature of all these entities, with the exception of C3 nephritic factor, causation was largely unknown. Over the next two decades, increasing attention was paid to the composition of the deposits detected by immunofluorescence. Type I was typically characterized by deposits of immunoglobulin as well as complement components; type II was distinguished by deposits of C3 only; the type III Burkholder variant typically had deposits of immunoglobulin and complement; whereas the type III Strife and Anders variant could manifest C3 either alone or in combination with immunoglobulins. As long as the pathogenesis of these forms remained obscure, the classification was cumbersome to use and perplexing to clinicians and pathologists alike. In the past decade, our understanding of the role of complement in the pathogenesis of MPGN has illuminated the field and led to a paradigm shift in classification (Figure 1). First, the observation that a number of patients with intramembranous dense deposits lack an MPGN pattern altogether caused the designation MPGN II to be discarded in favor of DDD. Second, pathologists began emphasizing in their reports the presence of isolated deposits of C3 in examples of MPGN type I and type III. A major breakthrough was the discovery of genetic mutations or deficiencies in complement-regulatory proteins in patients with isolated C3 deposits.4.Appel G.B. Cook H.T. Hageman G. et al.Membranoproliferative glomerulonephritis type II (dense deposit disease): an update.J Am Soc Nephrol. 2005; 16: 1392-1403Crossref PubMed Scopus (296) Google Scholar,5.Servais A. Fremeaux-Bacchi V. Lequintrec M. 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: 193-199Crossref PubMed Scopus (226) Google Scholar Thereafter, ‘C3 glomerulopathy’ assumed center stage as a newly recognized subgroup encompassing DDD and those examples of type I and type III (now termed ‘C3 glomerulonephritis’; C3GN) in which immunofluorescence reveals isolated deposits of C3, underscoring the pathogenetic importance of dysregulation of the alternative complement pathway. Thus, the modern approach to classification distinguishes those forms of MPGN with deposits of C3 only (known as C3 glomerulopathy and including both DDD and C3GN) from MPGN with deposits of immunoglobulin and complement.6.Sethi S. Fervenza F.C. Membranoproliferative glomerulonephritis: pathogenetic heterogeneity and proposal for a new classification.Semin Nephrol. 2011; 31: 341-348Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar The reports from Servais et al.7.Servais A. Noël 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; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar and Sethi et al.8.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar in this issue of Kidney International highlight the strengths and weaknesses of the term ‘C3 glomerulopathy.’ As validation of the classification, defective control of the alternative complement pathway was detectable in 71% of patients in the French cohort7.Servais A. Noël 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; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar (which included cases of C3GN, DDD, and MPGN type I) and 100% of those in the American cohort8.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar (which included cases of C3GN only). This defect can be due to mutations in complement proteins (such as C3, factor B, factor H, and factor I) or due to acquired autoantibodies that either stabilize the C3 convertase of the alternative pathway (e.g., C3 nephritic factors) or target the inhibitory complement factors (e.g., factor H autoantibodies). These abnormalities promote excessive activation of the alternative complement pathway in the fluid phase, with deposition of complement debris, including breakdown products of C3b and components of the terminal complement cascade, in the glomerular capillary wall. A reclassification of MPGN into immunoglobulin-mediated disease (prompting a work-up for infectious, autoimmune, or dysproteinemia-associated etiologies) vs. complement-mediated disease (prompting a work-up of the alternative pathway) should lead to better diagnostic and treatment algorithms and, ideally, improved outcomes in these diseases. For example, 9 of the 12 patients with C3GN in the American cohort were initially misclassified as having MPGN type I (n=4), MPGN type III (n=1), and postinfectious glomerulonephritis (n=4). The demonstration by Sethi et al.8.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar that the proteomic profile of C3GN by mass spectrometry is similar to that of DDD (with predominance of C3 and distal complement pathway components) further supports the emerging view that the presence of C3 alone is the major hallmark of alternative complement pathway dysregulation in C3 glomerulopathy, independent of histologic and ultrastructural features. However, the pitfall of lumping diseases into a single descriptor or category is an implied assumption of homogeneity. As compared with atypical hemolytic uremic syndrome, which is also strongly associated with dysregulated alternative complement pathway activity, C3 glomerulopathy manifests a much broader spectrum of clinical presentation, histopathology, genetic abnormalities, complement activity, and prognosis. Servais et al., looking only at the adult patients in their cohort, found worse 10–year renal survival in patients with DDD than in patients with MPGN type I and C3GN;7.Servais A. Noël 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; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar Sethi et al., in their smaller cohort, also report worse outcomes in DDD than in C3GN and suggest that C3GN may be a less aggressive entity.8.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar One possible explanation is the much higher rate of C3 nephritic factor (C3NeF) positivity in DDD (86.4% in the French cohort, in accordance with the approximately 80% rate described in other cohorts)9.Zhang Y. Meyer N.C. Wang K. et al.Causes of alternative pathway dysregulation in dense deposit disease.Clin J Am Soc Nephrol. 2012; 7: 265-274Crossref PubMed Scopus (140) Google Scholar than in C3GN (45.3% in the French cohort and 50% in the American cohort).7.Servais A. Noël 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; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar,8.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar Yet even this discrepancy is open to question, as Servais et al. report a fluctuation of the C3NeF activity in one-third of their patients during follow-up and a normal range of serum C3 levels in approximately 40% of C3NeF-positive patients, suggesting that the C3NeF-stabilized C3 convertase may be subject to regulation by other factors.7.Servais A. Noël 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; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar The authors hypothesize that complement-regulatory membrane cofactor protein (MCP) variants may explain this heterogeneity of disease in C3 glomerulopathy.7.Servais A. Noël 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; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar However, they are not able to show a functional role of their proposed at-risk MCP haplotype, and the P-values reported for the selected single-nucleotide polymorphisms in the MCP gene are not robust enough to denote significance, particularly without replication in an independent cohort.7.Servais A. Noël 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; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar One of the most intriguing findings to emerge from the French cohort is the identification of alternative complement pathway dysregulation in more than half of the 48 patients with MPGN type I.7.Servais A. Noël 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; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar In fact, a C3NeF was identified as frequently in MPGN type I as in C3GN. The terminology ‘C3 glomerulopathy’ is intended for immunoglobulin-negative diseases, to highlight the underlying alternative pathway dysregulation as opposed to activation of the classical pathway by antigen–antibody immune complexes. How, then, should we classify the MPGN type I patients described here with genetic abnormalities in factor H (n=5) or factor I (n=3) or with positive C3NeF activity (n=18)? One possible explanation is that these patients were previously misclassified as MPGN type I, akin to some patients in the American C3GN cohort, and that the immunoglobulin staining was trace and inconsequential; the lack of central review of all biopsies in this study, as the authors themselves acknowledge, is therefore a major limitation.7.Servais A. Noël 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; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar Small amounts of immunoglobulin may become trapped in areas of sclerosis or accumulate in podocyte protein resorption droplets, confounding immunofluorescence interpretation. However, if we are to accept that these cases truly have immunoglobulin deposits alongside serologic evidence of alternative pathway dysregulation, should we now consider these as yet another subtype of C3 glomerulopathy? These findings suggest more commonality between MPGN type I and C3 glomerulopathies than previously recognized and raise the question of whether patients with dysregulated alternative complement pathway may not also develop disease-causing immune deposits containing immunoglobulin and complement in the course of antigen-driven immune responses. Such observations are consistent with the predisposition to immune complex-mediated lupus nephritis in MRL-lpr mice with genetic deletion of complement factor H10.Bao L. Haas M. Quigg R.J. Complement factor H deficiency accelerates development of lupus nephritis.J Am Soc Nephrol. 2011; 22: 285-295Crossref PubMed Scopus (80) Google Scholar and the increased susceptibility to IgA nephropathy in people with mutations in the complement factor H locus on human chromosome 1q32.11.Gharavi A.G. Kiryluk K. Choi M. et al.Genome-wide association study identifies susceptibility loci for IgA nephropathy.Nat Genet. 2011; 43: 321-327Crossref PubMed Scopus (378) Google Scholar C3NeF has also been identified in some patients with postinfectious glomerulonephritis.12.Fremeaux-Bacchi V. Weiss L. Demouchy C. et al.Hypocomplementaemia of poststreptococcal acute glomerulonephritis is associated with C3 nephritic factor [C3NeF] IgG autoantibody activity.Nephrol Dial Transplant. 1994; 9: 1747-1750PubMed Google Scholar Because patients with complement-regulatory disorders are not protected from development of other immune-mediated glomerulonephritides, future studies will be needed to explore the potential contribution of alternative pathway complement dysregulation beyond C3 glomerulopathy. Screening tests of alternative complement pathway activity may help clear up some of this confusion and provide much-needed physiologic information supporting the diagnosis of C3 glomerulopathy. Sethi et al. used three different screening tests of the alternative pathway in their cohort of C3GN: a hemolytic assay, an alternative pathway functional assay, and levels of serum membrane attack complex.8.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathologic findings, complement abnormalities, glomerular proteomic profile, treatment and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar In such a small cohort, in which most patients showed remarkable stability of disease despite varied treatment regimens, it is impossible to discern whether these markers of alternative pathway activity are linked to outcomes. Such testing would likely have been far more informative in the larger French cohort but was not performed.7.Servais A. Noël 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; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar Instead, levels of C3 and C4 were used as baseline markers of complement activity, which by themselves are substandard in these complex diseases; not surprisingly, neither low C3 (<600mg/l) nor very low C3 (<200mg/l) levels were predictive of renal outcomes.7.Servais A. Noël 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; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar Wider access to the types of genetic and complement testing described in both studies should allow more etiology-specific diagnosis. Another provocative finding is the identification of both C3NeF and a genetic defect in the complement pathway in a proportion of patients in the French cohort: among 24 patients with an identified mutation in a complement gene, 13 also had detectable C3NeF.7.Servais A. Noël 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; 81: 454-463Abstract Full Text Full Text PDF Scopus (327) Google Scholar Why is there coexistence of inherited and acquired abnormalities of the alternative complement pathway in such cases? These numbers are difficult to ascribe to coincidence and raise the question of whether increased activity of the alternative complement pathway on a genetic basis might promote autoimmune phenomena by unbridled activation (and perhaps conformational change) of the C3 convertase. These findings suggest a two-hit disease model in some people. Larger cohorts are needed to evaluate the prevalence of this phenomenon and the implications for evidence-based treatment." @default.
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• W2064717040 title "C3 glomerulopathy: what's in a name?" @default.
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