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UPDATE ON C3 glomerulopathy

NDT Advance Access published October 17, 2014

NephrolDialTransplant(2014)0:1–9doi:10.1093/ndt/gfu317

FullReview

UpdateonC3glomerulopathy

ThomasD.Barbour,MarietaM.RusevaandMatthewC.Pickering

CentreforComplementandIn ammationResearch(CCIR),DivisionofImmunologyandIn ammation,DepartmentofMedicine,ImperialCollegeLondon,LondonW120NN,UK

Correspondenceandoffprintrequeststo:ThomasD.Barbour;E-mail:t.barbour@imperial.ac.uk

ABSTRACT

microscopy’[1].Itoftenprogressestoend-stagekidneydisease(ESKD)andrecursafterrenaltransplantation.TheC3glomerulopathyreferstoadiseaseprocessinwhichabnor-prototypicalformofC3glomerulopathyisdensedepositmalcontrolofcomplementactivation,degradationordepos-disease(DDD),whichhistoricallyhasbeendiagnosedbaseditionresultsinpredominantC3fragmentdepositionwithinonlinear,hyperosmiophilicelectron-densedepositsoccupyingtheglomerulusandglomerulardamage.Recentstudieshavethemiddlelayeroftheglomerularbasementmembraneimprovedourunderstandingofitspathogenesis.Thekeyab-(GBM).‘C3glomerulonephritis’(C3GN)referstothosecasesnormalityisuncontrolledC3bampli cationinthecirculationofC3glomerulopathyinwhichtheelectron-densedepositsdoand/oralongtheglomerularbasementmembrane.Familynothavethisclassicappearance.

studiesinwhichdiseasesegregateswithstructurallyabnormalOnestrikingobservationinpatientswithC3glomerulopa-complementfactorH-related(CFHR)proteinsdemonstratethyishowcommonlyclinicalpresentationisprecededbyanthatabnormalCFHRproteinsareimportantinsometypesofinfectiousepisode.ThissuggeststhatinfectionmayinitiateorC3glomerulopathy.Thisiscurrentlythoughttobeduetotheexacerbatethediseaseprocess,forexamplebyactingasanex-abilityoftheseproteinstoantagonizethemajornegativeregu-ogenoustriggerofC3activation.OnceC3isactivated,abnor-latorofC3activation,complementfactorH(CFH),aprocessmalglomerularaccumulationofC3fragmentsoccursduetotermed‘CFHde-regulation’.RecentclinicopathologicalcohortuncontrolledC3bampli cationviathealternativepathwaystudieshaveledtofurtherre nementsincasede nition,cul-(AP).InthemajorityofpatientswithC3glomerulopathy,ac-minatingina2013consensusreport,whichprovidesrecom-quiredorgeneticdefectsinAPregulationcanbedemon-mendationsregardinginvestigationandtreatment.Earlystrated.In2013,aconsensusreportinC3glomerulopathywasclinicalexperiencewithcomplement-targetedtherapeutics,publishedwithrecommendationsregardingcasede nition,notablyC5inhibitors,hasalsonowbeenpublished.Here,weinvestigationandtreatment[1].Atpresent,allpatientsinsummarizethelatestdevelopmentsinC3glomerulopathy.whomC3glomerulopathyisdiagnosedoneithernativeortransplantkidneybiopsyshouldbeinvestigatedforlowplasmaKeywords:C3glomerulopathy,complement,densedeposit,levelsofC3,C4andcomplementfactorH(CFH),andthefactorH

presenceofparaprotein(i.e.monoclonalgammopathy),C3nephriticfactorandabnormalcomplementfactorH-relatedprotein5(CFHR5).

INTRODUCTION

CFHisthemainplasmaregulatoroftheAPandconsistsof20proteinsubunits,termedshortconsensusrepeat(SCR)C3glomerulopathydesignates‘adiseaseprocessduetoabnor-domains,thatareencodedwithintheregulatorsofcomple-malcontrolofcomplementactivation,deposition,ordegrad-ment(RCA)geneclusteronchromosome1q32.TheCFH–ationandcharacterizedbypredominantglomerularC3CFHRproteinfamily(Figure1A)comprisesCFHand vefragmentdepositionwithelectron-densedepositsonelectron

structurallyrelatedCFHRproteinsthatareencodeddown-©TheAuthor2014.PublishedbyOxfordUniversityPressonbehalfofERA-streamoftheCFHgene.FrequentinterspersedrepeatelementsEDTA.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeacrosstheCFH–CFHRlocuspredisposeto

UPDATE ON  C3 glomerulopathy

genomic

CommonsAttributionNon-CommercialLicense(http://www.wendangxiazai.com/licenses/by-nc/4.0/),whichpermitsnon-commercialre-use,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.Forcommercialre-use,pleasecontactjournals.permissions@http://www.wendangxiazai.com

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