Novel roles of complement in renal diseases and their therapeutic consequences
2013; Elsevier BV; Volume: 84; Issue: 3 Linguagem: Inglês
10.1038/ki.2013.134
ISSN1523-1755
AutoresTakehiko Wada, Masaomi Nangaku,
Tópico(s)Blood groups and transfusion
ResumoThe complement system functions as a part of the innate immune system. Inappropriate activation of the complement pathways has a deleterious effect on kidneys. Recent advances in complement research have provided new insights into the pathogenesis of glomerular and tubulointerstitial injury associated with complement activation. A new disease entity termed ‘C3 glomerulopathy’ has recently been proposed and is characterized by isolated C3 deposition in glomeruli without positive staining for immunoglobulins. Genetic and functional studies have demonstrated that several different mutations and disease variants, as well as the generation of autoantibodies, are potentially associated with its pathogenesis. The data from comprehensive analyses suggest that complement dysregulation can also be associated with hemolytic uremic syndrome and more common glomerular diseases, such as IgA nephropathy and diabetic kidney disease. In addition, animal studies utilizing genetically modified mice have begun to elucidate the molecular pathomechanisms associated with the complement system. From a diagnostic point of view, a noninvasive, MRI-based method for detecting C3 has recently been developed to serve as a novel tool for diagnosing complement-mediated kidney diseases. While novel therapeutic tools related to complement regulation are emerging, studies evaluating the precise roles of the complement system in kidney diseases will still be useful for developing new therapeutic approaches. The complement system functions as a part of the innate immune system. Inappropriate activation of the complement pathways has a deleterious effect on kidneys. Recent advances in complement research have provided new insights into the pathogenesis of glomerular and tubulointerstitial injury associated with complement activation. A new disease entity termed ‘C3 glomerulopathy’ has recently been proposed and is characterized by isolated C3 deposition in glomeruli without positive staining for immunoglobulins. Genetic and functional studies have demonstrated that several different mutations and disease variants, as well as the generation of autoantibodies, are potentially associated with its pathogenesis. The data from comprehensive analyses suggest that complement dysregulation can also be associated with hemolytic uremic syndrome and more common glomerular diseases, such as IgA nephropathy and diabetic kidney disease. In addition, animal studies utilizing genetically modified mice have begun to elucidate the molecular pathomechanisms associated with the complement system. From a diagnostic point of view, a noninvasive, MRI-based method for detecting C3 has recently been developed to serve as a novel tool for diagnosing complement-mediated kidney diseases. While novel therapeutic tools related to complement regulation are emerging, studies evaluating the precise roles of the complement system in kidney diseases will still be useful for developing new therapeutic approaches. The complement system is a cascade of proteins that mediate important innate immune functions, but this system’s inappropriate activation has been implicated in kidney disease. In this review, we discuss recent advances for identifying the roles of complement activation in the development and progression of kidney disease. The complement system, which is an important mediator of inflammation and tissue injury, is a family of more than 20 serum and cell-surface proteins that function as a cascade (Figure 1). Immune complexes formed by IgG and nephritogenic antigens bind to complement factor C1q and activate the C1 complex, leading to the formation of C3 convertase and the enzymatic cleavage of the central complement component C3. C3 activation results in the release of the chemotactic factor C3a and covalent attachment of the C3b fragment to host cells, which is an important step for amplification through the alternative pathway and for continued formation of the terminal membrane attack complex C5b-9. Under normal conditions, complement activation is strictly regulated by a series of circulating and cell-bound complement regulatory proteins. Complement activation induces inflammation and damages the host through the production of chemotactic factors. C3a and C5a function in a synergistic manner with Fc-receptor cross-linking to stimulate inflammatory cells. Interestingly, a recent study by Karsten et al.1.Karsten C.M. Pandey M.K. Figge J. et al.Anti-inflammatory activity of IgG1 mediated by Fc galactosylation and association of FcgammaRIIB and dectin-1.Nat Med. 2012; 18: 1401-1406Crossref PubMed Scopus (315) Google Scholar has demonstrated novel regulatory mechanisms for complement-FcγR cross talk. They have demonstrated that immune complexes with highly galactosylated IgG suppress the C5a receptor (C5aR)–mediated inflammatory response by promoting an interaction between the inhibitory IgG receptor FcγRIIB and the C-type lectin-like receptor dectin-1. Thus, the inhibitory effect of highly galactosylated IgG–immune complexes may serve as a feedback loop to control complement- and chemokine-mediated inflammation. The nephritogenic effects of complement activation are also mediated by the generation of the membrane attack complex C5b-9. Although C5b-9 creates pores in the cell membrane and lyses cells without nuclei, such as erythrocytes, C5b-9 induces the activation of nucleated cells, converting resident kidney cells into effector cells to cause injury. Recent advances in complement research have revealed an unexpected role for complement. Komuro and colleagues2.Naito A.T. Sumida T. Nomura S. et al.Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes.Cell. 2012; 149: 1298-1313Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar reported that C1q has a role in impairing the regenerative capacity of skeletal muscle in aged animals by activating canonical Wnt signaling, which was induced by cleavage of LRP6, a Wnt coreceptor. This finding is important, because it suggests that the complement system may be associated with aging and that the modulation of C1q-dependent activation of Wnt signaling may provide a therapeutic option for diseases related to dysregulated Wnt signaling. Histological findings in renal biopsy specimens provide important information for diagnosing kidney diseases, but renal biopsy is an invasive procedure. Recently, Thurman and colleagues3.Sargsyan S.A. Serkova N.J. Renner B. et al.Detection of glomerular complement C3 fragments by magnetic resonance imaging in murine lupus nephritis.Kidney Int. 2012; 81: 152-159Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar developed an magnetic resonance imaging–based method for detecting glomerular C3. By using this method, they tracked glomerular C3b/iC3b/C3d deposition in the MRL/lpr mouse model of lupus nephritis, using superparamagnetic iron oxide nanoparticles conjugated to complement receptor type 2 as a targeting agent. This noninvasive measure of complement activation in the kidney using magnetic resonance imaging may be a good biomarker of disease. C1q nephropathy is defined by conspicuous C1q in glomerular immune deposits in patients with no evidence of systemic lupus erythematosus or membranoproliferative glomerulonephritis (MPGN) type I. Vizjak et al.4.Vizjak A. Ferluga D. Rozic M. et al.Pathology, clinical presentations, and outcomes of C1q nephropathy.J Am Soc Nephrol. 2008; 19: 2237-2244Crossref PubMed Scopus (68) Google Scholar described the clinicopathologic correlations and outcomes for 72 patients with C1q nephropathy. The light microscopic findings included focal segmental glomerulosclerosis, proliferative glomerulonephritis, and various other lesions. The clinical presentations were heterogenous even within a patient group with the same histological lesion. The mechanisms underlying C1q nephropathy include C1q binding to poly-anionic substances (DNA, RNA, Gram-negative bacterial proteins, viral proteins, etc.) or to C1q receptors, C1q production by dendritic cells and macrophages, and C1 inhibitor abnormalities.5.Mii A. Shimizu A. Masuda Y. et al.Current status and issues of C1q nephropathy.Clin Exp Nephrol. 2009; 13: 263-274Crossref PubMed Scopus (32) Google Scholar At this point, there is no specific therapy for C1q nephropathy, and patients with C1q nephropathy may be treated with the protocols for the underlying microscopic lesions, such as minimal-change disease or focal segmental glomerulosclerosis. MPGN is generally characterized by mesangial interposition and the duplication of glomerular basement membranes, which are typically associated with immune deposits in the peripheral capillary walls. MPGN was initially classified into three types based on electron microscopic findings. MPGN type I is characterized by a membranoproliferative phenotype with subendothelial and mesangial deposits.6.Levy M. Gubler M.C. Sich M. et al.Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (Type I MPGN).Clin Immunol Immunopathol. 1978; 10: 477-492Crossref PubMed Scopus (40) Google Scholar In MPGN type II, also known as dense deposit disease (DDD), highly electron-dense intramembranous and mesangial deposits were the histopathological hallmarks.7.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 (168) Google Scholar MPGN type III is characterized by subendothelial and subepithelial (Burkholder subtype) deposits or complex intramembranous, subendothelial, and subepithelial deposits with fraying of the lamina densa (Strife and Anders subtype).8.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 However, because our understanding of the pathogenesis of MPGN has illuminated the field, the classification is now being replaced with a more mechanistic classification based on the presence of immunoglobulins and/or C3 deposits by immunofluorescence microscopy.9.Sethi S. Nester C.M. Smith R.J. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.Kidney Int. 2012; 81: 434-441Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar Recently, Pickering and colleagues10.Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (264) Google Scholar proposed that glomerulonephritis characterized by the presence of C3 in the absence of immunoglobulins or components of the classical pathway of complement activation (C1q and C4) should be called ‘C3 glomerulopathy.’ C3 glomerulopathy is a disease entity that includes DDD and C3 glomerulonephritis, both of which result from the dysregulation of the alternative pathway.9.Sethi S. Nester C.M. Smith R.J. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.Kidney Int. 2012; 81: 434-441Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 10.Fakhouri F. Fremeaux-Bacchi V. Noel L.H. et al.C3 glomerulopathy: a new classification.Nat Rev Nephrol. 2010; 6: 494-499Crossref PubMed Scopus (264) Google Scholar, 11.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 (239) Google Scholar, 12.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, 13.Sethi S. Gamez J.D. Vrana J.A. et al.Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway.Kidney Int. 2009; 75: 952-960Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 14.Sethi S. Fervenza F.C. Zhang Y. et al.Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement.Clin J Am Soc Nephrol. 2011; 6: 1009-1017Crossref PubMed Scopus (121) Google Scholar, 15.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 (154) Google Scholar, 16.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 17.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 (371) Google Scholar DDD and C3 glomerulonephritis may be difficult to distinguish from each other by light microscopic and immunofluorescence studies. However, electron microscopy shows mesangial and/or subendothelial, intramembranous, and subepithelial deposits in C3 glomerulonephritis, whereas dense osmiophilic deposits are present along the glomerular basement membranes in DDD. Dense deposit disease. DDD was originally classified as MPGN type II. However, an analysis of 81 DDD cases showed five different pathological patterns: membranoproliferative, mesangial proliferative, crescentic, acute proliferative, and exudative.18.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 Sethi et al.13.Sethi S. Gamez J.D. Vrana J.A. et al.Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway.Kidney Int. 2009; 75: 952-960Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar used mass spectrometry to analyze glomeruli isolated by laser-capture microdissection and showed that they contain components of the alternative pathway of complement activation and components of the terminal pathway C5–C9. An analysis of 32 patients with biopsy-proven DDD revealed a mechanism of inappropriate alternative pathway activation. Twenty-five patients (78%) were positive for C3 nephritic factors, which are autoantibodies to C3Bb that stabilize C3 convertase leading to C3 consumption and persistent activation of the alternative pathway.15.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 (154) Google Scholar A study on a large French cohort, including 29 biopsy-proven DDD,17.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 (371) Google Scholar revealed that more than half of the patients had a low C3 level and a normal C4 level, suggesting activation of the alternative pathway. C3Nef was detected in 86.4% of DDD patients, which is comparable to the data from other studies.11.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 (239) Google Scholar, 15.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 (154) Google Scholar, 16.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 19.Nasr S.H. Valeri A.M. Appel G.B. et al.Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.Clin J Am Soc Nephrol. 2009; 4: 22-32Crossref PubMed Scopus (132) Google Scholar Genetic defects were found in five patients, and all of them had different mutations in the gene coding for factor H (CFH gene). Genotyping for selected single-nucleotide polymorphisms implicated CFH Y402H as a significant risk variant, as other studies have reported.14.Sethi S. Fervenza F.C. Zhang Y. et al.Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement.Clin J Am Soc Nephrol. 2011; 6: 1009-1017Crossref PubMed Scopus (121) Google Scholar,20.Abrera-Abeleda M.A. Nishimura C. Smith J.L. et al.Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease).J Med Genet. 2006; 43: 582-589Crossref PubMed Scopus (179) Google Scholar Other potential causes included autoantibodies against factor B and factor H, which also lead to alternative pathway dysregulation. The recent development of sensitive and specific assays for C3 nephritic factor will provide a rational approach to detect and characterize nephritic factors.21.Paixao-Cavalcante D. Lopez-Trascasa M. Skattum L. et al.Sensitive and specific assays for C3 nephritic factors clarify mechanisms underlying complement dysregulation.Kidney Int. 2012; 82: 1084-1092Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Martinez-Barricarte et al.12.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 identified a family in which a mother and her two identical twin sons with DDD had a two-amino-acid deletion in the MG7 domain of C3 (923ΔDG). This mutant form of C3 is resistant to cleavage by C3 convertase and cannot form activated C3b. They found that C3Δ923DG convertase derived from the mutant C3 was resistant to factor H–mediated regulation and that active forms of C3 with the mutation were resistant to factor I–mediated proteolysis. These results suggest that these two amino acids in C3 are crucial for the normal regulation of complement activation.12.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 C3 glomerulonephritis/CFHR5 nephropathy. Another C3 glomerulopathy variant termed C3 glomerulonephritis has also been characterized by glomerular deposits of C3 without immunoglobulins.11.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 (239) Google Scholar,22.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 (138) Google Scholar This disorder equally affects all ages and both genders, and it typically presents with hematuria and proteinuria. Renal function remains stable in most of the patients. Functional and genetic studies of the alternative pathway have identified heterogenous abnormalities that lead to increased alternative pathway activity, including C3 nephritic factors, factor H autoantibodies, and mutations in the genes involved in complement regulation, such as CFH and CFI (coding for factor I). The mutations found in these patients include a frameshift in CFH and missense variants in exon 6 of CFI and CFHR5. The remaining patients carried CFH variants associated with increased baseline activity of the alternative pathway. Furthermore, a mass spectrometric analysis of laser-dissected glomeruli from those patients demonstrated an accumulation of alternative pathway and terminal complement complex proteins. Another group has reported different mutations in CFH and CFI from patients with C3 glomerulonephritis.17.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 (371) Google Scholar These findings suggest that C3 glomerulonephritis results from diverse abnormalities in the alternative complement pathway, leading to subsequent glomerular injury. A familial form of this disease has been described as CFHR5 nephropathy.23.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 CFHR5 is one of the five complement factor H–related proteins. Gale et al.23.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 identified two families, both of which originated from Cyprus, with segregated autosomal dominant microscopic hematuria. Renal biopsies revealed lesions compatible with C3 glomerulopathy. Genome-wide linkage and candidate gene analyses revealed that the disease cosegregated with a mutation in the CFHR5 gene. The mutant CFHR5 protein binds to C3b less effectively than wild-type CFHR5, suggesting that this mutant form might increase C3 convertase activity and promote complement system function. Athanasiou et al.24.Athanasiou Y. Voskarides K. Gale D.P. et al.Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.Clin J Am Soc Nephrol. 2011; 6: 1436-1446Crossref PubMed Scopus (109) Google Scholar have recently expanded on this study, reporting on the histological, molecular, and clinical findings in 91 mutation carriers from 16 families with the same founder mutation. They demonstrated that 23 of the 43 male carriers (53.5%), as well as 5 of the 48 female carriers (10.4%), developed kidney failure, suggesting a marked gender difference in renal prognosis. Autosomal dominant, complement-mediated glomerulonephritis associated with abnormal increases in copy number across the CFHR3 and CFHR1 loci was recently reported. In addition to normal copies of these genes, affected individuals carry a unique hybrid CFHR3-1 gene and develop familial C3 nephropathy.25.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 Diagnostic value for genetic testing. Accumulating evidence, including that mentioned above, suggests that genetic testing may be valuable to diagnose C3 glomerulopathy associated with alternative pathway activation. However, there is a wide variety of mutations/variants even in a single gene, and the relationship between the mutations and functional consequences are still unclear. Moreover, there are some mutations that are common between C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS), suggesting that the mutations in the genes coding the alternative pathway complement components do not solely determine the disease phenotype (Table 1).Table 1Representative abnormalities in complement leading to renal diseaseComponents/related moleculesDiseases/phenotypesSpeciesNotesReferencesComplement C3C3 glomerulopathy (DDD)HumanMutation (923ΔDG)12.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 ScholaraHUSHumanMutations50.Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google ScholarFactor HC3 glomerulopathy (DDD/C3GN)HumanMutations11.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 (239) Google Scholar, 14.Sethi S. Fervenza F.C. Zhang Y. et al.Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement.Clin J Am Soc Nephrol. 2011; 6: 1009-1017Crossref PubMed Scopus (121) Google Scholar, 15.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 (154) Google Scholar, 16.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 20.Abrera-Abeleda M.A. Nishimura C. Smith J.L. et al.Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease).J Med Genet. 2006; 43: 582-589Crossref PubMed Scopus (179) Google ScholaraHUSHumanMutations49.Warwicker P. Goodship T.H. Donne R.L. et al.Genetic studies into inherited and sporadic hemolytic uremic syndrome.Kidney Int. 1998; 53: 836-844Abstract Full Text Full Text PDF PubMed Scopus (419) Google ScholarFactor IC3 glomerulopathy (C3GN)HumanMutations11.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 (239) Google Scholar,16.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (213) Google ScholaraHUSHumanMutations50.Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google ScholarMCPaHUSHumanMutations50.Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google ScholarFactor BaHUSHumanMutations50.Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google ScholarCFHR5Familial C3 glomerulopathy (CFHR5 nephropathy)HumanMutation (internal duplication)23.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,24.Athanasiou Y. Voskarides K. Gale D.P. et al.Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.Clin J Am Soc Nephrol. 2011; 6: 1436-1446Crossref PubMed Scopus (109) Google ScholarCFHR3-1Familial C3 glomerulopathyHumanMutation (hybrid gene)25.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 ScholarCFHR1/3IgA nephropathyHumanCombined deletion37.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 (443) Google ScholaraHUSHumanCombined deletion50.Noris M. Remuzzi G. Atypical hemolytic-uremic syndrome.N Engl J Med. 2009; 361: 1676-1687Crossref PubMed Scopus (928) Google ScholarFactor B autoantibodyC3 glomerulopathy (DDD)HumanPositive in serum15.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 (154) Google ScholarFactor H autoantibodyC3 glomerulopathy (DDD/C3GN)HumanPositive in serum15.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 (154) Google Scholar,16.Sethi S. Fervenza F.C. Zhang Y. et al.C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.Kidney Int. 2012; 82: 465-473Abstract Full Text Full Text PDF PubMed Scopus (213) Google ScholarC3NefC3 glomerulopathy (DDD/C3GN)HumanPositive in serum6.Levy M. Gubler M.C. Sich M. et al.Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (Type I MPGN).Clin Immunol Immunopathol. 1978; 10: 477-492Crossref PubMed Scopus (40) Google Scholar, 9.Sethi S. Nester C.M. Smith R.J. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion.Kidney Int. 2012; 81: 434-441Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 11.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;
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