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Dense Deposit Disease and C3 Glomerulopathy

      Summary

      C3 glomerulopathy refers to those renal lesions characterized histologically by predominant C3 accumulation within the glomerulus, and pathogenetically by aberrant regulation of the alternative pathway of complement. Dense deposit disease is distinguished from other forms of C3 glomerulopathy by its characteristic appearance on electron microscopy. The extent to which dense deposit disease also differs from other forms of C3 glomerulopathy in terms of clinical features, natural history, and outcomes of treatment including renal transplantation is less clear. We discuss the pathophysiology of C3 glomerulopathy, with evidence for alternative pathway dysregulation obtained from affected individuals and complement factor H (Cfh)-deficient animal models. Recent linkage studies in familial C3 glomerulopathy have shown genomic rearrangements in the Cfh-related genes, for which the novel pathophysiologic concept of Cfh deregulation has been proposed.

      Keywords

      In 1962 the renal pathologist, Berger, and electron microscopist, Galle, published the first description of dense deposit disease (DDD), based on needle biopsies performed in three patients at the Necker Hospital in Paris.
      • Berger J.
      • Galle P.
      Altération singulière des membranes basales du rein.
      They later extended their observations to a total of 14 patients.
      • Berger J.
      • Galle P.
      Dépôts denses au sein des membranes basales du rein: étude en microscopies optique et électronique.
      DDD is a rare lesion, so named because of the appearance on electron microscopy (EM) of extremely dark, ribbon-like, electron-dense material in the central layer (lamina densa) of the glomerular basement membrane (GBM). Deposits also may occur in the mesangium, Bowman’s capsule, and tubular basement membrane. DDD has variable morphology on light microscopy (LM), with a mesangioproliferative
      • Walker P.D.
      • Ferrario F.
      • Joh K.
      • Bonsib S.M.
      Dense deposit disease is not a membranoproliferative glomerulonephritis.
      or membranoproliferative
      • Nasr S.H.
      • Valeri A.M.
      • Appel G.B.
      • Sherwinter J.
      • Stokes M.B.
      • Said S.M.
      • et al.
      Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.
      • Wang J.
      • Tang Z.
      • Luo C.
      • Hu Y.
      • Zeng C.
      • Chen H.
      • et al.
      Clinical and pathological features of dense deposit disease in Chinese patients.
      appearance being most common. Other patterns including endocapillary proliferative and crescentic are described in both native disease and post-transplant recurrence.
      • Braun M.C.
      • Stablein D.M.
      • Hamiwka L.A.
      • Bell L.
      • Bartosh S.M.
      • Strife C.F.
      Recurrence of membranoproliferative glomerulonephritis type II in renal allografts: the North American Pediatric Renal Transplant Cooperative Study experience.
      DDD is therefore a more accurate name for this lesion than membranoproliferative glomerulonephritis (MPGN) type 2.
      • Habib R.
      • Kleinknecht C.
      • Gubler M.C.
      • Maïz H.B.
      Idiopathic membranoproliferative glomerulonephritis. Morphology and natural history.
      Immunofluorescence (IF) or immunohistochemistry (IHC) typically shows intense glomerular C3 staining with little or no immunoglobulin (Ig).
      • Berger J.
      • Yaneva H.
      • Antoine B.
      Étude immunohistochimique des lésions glomérulaires.
      However, this appearance is not specific for DDD, with one early French series of 49 patients with MPGN comprising 15 patients with isolated or predominant glomerular C3 staining, of whom only 5 patients had intramembranous dense deposits characteristic of DDD.
      • Bariéty J.
      • Druet P.
      • Loirat P.
      • Lagrue G.
      Les glomérulonéphrites pariétoprolifératives glomerulonephritis (G.N.P.P). Étude histopathologique en microcopie optique, électronique et en immunohistochimie de 49 cas. Corrélations anatomocliniques.
      In a 2007 French series of 19 patients, Servais et al
      • Servais A.
      • Frémeaux-Bacchi V.
      • Lequintrec M.
      • Salomon R.
      • Blouin J.
      • Knebelmann B.
      • et al.
      Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.
      introduced the term C3 glomerulonephritis (C3GN) to describe isolated glomerular C3 without intramembranous deposits. Accordingly, the term C3 glomerulopathy was proposed
      • Fakhouri F.
      • Frémeaux-Bacchi V.
      • Noël L.H.
      • Cook H.T.
      • Pickering M.C.
      C3 glomerulopathy: a new classification.
      for all glomerular lesions, including DDD, that are characterized by predominant C3 accumulation within the glomerulus using IF/IHC. The presence of predominant or isolated C3 accumulation suggests activation of the alternative pathway (AP) of complement, and many cases of C3 glomerulopathy show genetic or acquired AP dysregulation.
      Recognizable entities within C3 glomerulopathy include those with characteristic morphologic appearances (DDD and electron-dense intramembranous GBM transformation) and those with clear etiology (complement factor H-related 5 [CFHR5] nephropathy and the presence of an abnormal CFHR5 protein). Because postinfectious GN typically is characterized by a reversible decrease in serum C3 and the presence of glomerular C3 without Ig, differentiation from C3 glomerulopathy sometimes may be possible only with knowledge of the clinical course. In a number of cases in which there has been persistent renal disease after diagnosis of postinfectious GN, AP abnormalities have been detected and subsequent biopsy specimens were consistent with C3 glomerulopathy.
      • Vernon K.A.
      • Goicoechea de Jorge E.
      • Hall A.E.
      • Frémeaux-Bacchi V.
      • Aitman T.J.
      • Cook H.T.
      • et al.
      Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency.
      • Sandhu G.
      • Bansal A.
      • Ranade A.
      • Jones J.
      • Cortell S.
      • Markowitz G.S.
      C3 glomerulopathy masquerading as acute postinfectious glomerulonephritis.
      • Sethi S.
      • Fervenza F.C.
      • Zhang Y.
      • Zand L.
      • Meyer N.C.
      • Borsa N.
      • et al.
      Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement.
      • Meleg-Smith S.
      The many faces of C3 glomerulopathy.
      This includes a report of a young girl with acute post-streptococcal GN and low serum C3 levels in whom recurrent macroscopic hematuria prompted biopsy examinations 9 and 20 months after the initial presentation.
      • Vernon K.A.
      • Goicoechea de Jorge E.
      • Hall A.E.
      • Frémeaux-Bacchi V.
      • Aitman T.J.
      • Cook H.T.
      • et al.
      Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency.
      The biopsy specimens showed MPGN, with IHC showing capillary wall and mesangial C3 without Ig or C1q, and EM showing intramembranous and mesangial deposits. A heterozygous sequence variant in the CFHR5 gene, in which duplication of a single nucleotide resulted in a premature stop codon, later was identified in the girl and her unaffected mother. Notwithstanding some common pathogenetic associations, atypical hemolytic uremic syndrome (aHUS) is not considered a C3 glomerulopathy because endothelial injury usually is seen without significant C3 deposition or electron-dense deposits.
      • Pickering M.C.
      • Cook H.T.
      Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals.

      Histologic Features

      Electron-dense deposits are seen within the glomerulus in all forms of C3 glomerulopathy. DDD is defined by the intramembranous location of these deposits, their intensely osmiophilic appearance forming ribbons, and the associated transformation of the GBM (Fig. 1). Confirmation of DDD requires EM, although the diagnosis can be suspected with a high degree of confidence if the typical LM and IF/IHC features are present. The distinction between DDD and C3GN is sometimes difficult even using EM,
      • Sethi S.
      • Fervenza F.C.
      • Zhang Y.
      • Nasr S.H.
      • Leung N.
      • Vrana J.
      • et al.
      Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement.
      • Bridoux F.
      • Desport E.
      • Frémeaux-Bacchi V.
      • Chong C.F.
      • Gombert J.M.
      • Lacombe C.
      • et al.
      Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association?.
      • Hawfield A.
      • Iskandar S.S.
      • Smith R.J.
      Alternative pathway dysfunction in kidney disease: a case report and review of dense deposit disease and C3 glomerulopathy.
      with debates about the extent of intramembranous deposits required for EM diagnosis of DDD.

      Strife CF, West CD, Witte DP. Crescentic glomerulonephritis in childhood: acute nonproliferative glomerulitis versus dense deposit disease. Am J Kidney Dis. 2003;41:897; author reply 898.

      Furthermore, because the ribbons of DDD typically are discontinuous and may be more prominent in some capillary loops than others, they may be missed as a result of biopsy sampling error, leading to a diagnosis of C3GN. Such discrepancies may be important in the context of prognostic or therapeutic studies comparing outcomes in DDD and C3GN.
      Figure thumbnail gr1
      Figure 1Renal histology in individuals with DDD. (A) Light microscopy with silver stain showing a membranoproliferative pattern with double contours of the GBM. (B) Immunofluorescence and (C) immunohistochemistry with immunoperoxidase showing strong capillary wall staining of C3 and some granular mesangial C3. (D) Characteristic sausage-like, intramembranous, osmiophilic deposits on electron microscopy. Reprinted with permission from Dr. C. Nast.
      The ultrastructural characteristics of C3GN are less clearly defined, other than by the absence of the hallmarks of DDD (Fig. 2). In the original French C3GN series by Servais et al,
      • Servais A.
      • Frémeaux-Bacchi V.
      • Lequintrec M.
      • Salomon R.
      • Blouin J.
      • Knebelmann B.
      • et al.
      Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.
      two main histologic groups were described. The first group had typical features of MPGN type 1, with mesangial proliferation, double contours, and subendothelial, mesangial, and (less commonly) subepithelial deposits. The second group lacked mesangial proliferation, a membranoproliferative pattern, or subendothelial deposits. EM was performed in only two patients (confirming the absence of dense intramembranous deposits).
      • Servais A.
      • Frémeaux-Bacchi V.
      • Lequintrec M.
      • Salomon R.
      • Blouin J.
      • Knebelmann B.
      • et al.
      Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome.
      This series recently was updated to provide data on 29 DDD patients, 56 C3GN patients, and 49 MPGN type 1 patients (both adults and children).
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      Occasionally, the EM appearance of C3GN closely resembles that previously described as a subtype of MPGN type 3 by Strife et al.
      • Strife C.F.
      • McEnery P.T.
      • McAdams A.J.
      • West C.D.
      Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane.
      In CFHR5 nephropathy, histologic appearances (Fig. 2E and F) include mesangial and/or capillary wall C3 deposits on IF; a normal or mesangioproliferative pattern on LM; and mesangial, subendothelial, and occasional subepithelial deposits of only moderate density on EM. Subepithelial deposits may in fact be present in all types of C3 glomerulopathy, sometimes with so-called humps identical to those characteristically seen in postinfectious GN. In one DDD series, paramesangial subepithelial deposits correlated with low serum C3 owing to C3 nephritic factor (C3NeF) activity
      • West C.D.
      • Witte D.P.
      • McAdams A.J.
      Composition of nephritic factor-generated glomerular deposits in membranoproliferative glomerulonephritis type 2.
      and were composed of C3c.
      • West C.D.
      • McAdams A.J.
      Paramesangial glomerular deposits in membranoproliferative glomerulonephritis type II correlate with hypocomplementemia.
      Laser microdissection and mass spectrometry of glomerular tissue has shown a similar proteomic profile for DDD
      • Sethi S.
      • Gamez J.D.
      • Vrana J.A.
      • Theis J.D.
      • Bergen III, H.R.
      • Zipfel P.F.
      • et al.
      Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway.
      and C3GN
      • Sethi S.
      • Fervenza F.C.
      • Zhang Y.
      • Nasr S.H.
      • Leung N.
      • Vrana J.
      • et al.
      Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement.
      that includes alternative and terminal pathway complement components.
      Figure thumbnail gr2
      Figure 2Renal histology in individuals with C3GN. (A) Light microscopy showing a membranoproliferative pattern with segmental endocapillary neutrophil infiltration. (B) Electron microscopy showing moderately dense capillary wall and mesangial deposits. (C) Light microscopy showing mesangial expansion and (D) immunoperoxidase showing mesangial C3 in the same individual. (E) Immunoperoxidase showing granular capillary wall C3, in this case without conspicuous mesangial deposits, and (F) electron microscopy showing predominantly subendothelial deposits (and a transmembranous deposit) in an individual with CFHR5 nephropathy.

      Clinical Features

      DDD has an estimated prevalence of 2 to 3 per million population
      • Smith R.J.
      • Harris C.L.
      • Pickering M.C.
      Dense deposit disease.
      and traditionally is viewed as a diagnosis of childhood and young adulthood.
      • Galle P.
      • Mahieu P.
      Electron dense alteration of kidney basement membranes. A renal lesion specific of a systemic disease.
      Several series have shown a significantly younger mean age at diagnosis among DDD patients compared with MPGN types 1/3
      • Donadio Jr, J.V.
      • Slack T.K.
      • Holley K.E.
      • Ilstrup D.M.
      Idiopathic membranoproliferative (mesangiocapillary) glomerulonephritis: a clinicopathologic study.
      • Cameron J.S.
      • Turner D.R.
      • Heaton J.
      • Williams D.G.
      • Ogg C.S.
      • Chantler C.
      • et al.
      Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis.
      • Little M.A.
      • Dupont P.
      • Campbell E.
      • Dorman A.
      • Walshe J.J.
      Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk.
      or C3GN.
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      However, some DDD cohorts have comprised numerous older patients,
      • Swainson C.P.
      • Robson J.S.
      • Thomson D.
      • MacDonald M.K.
      Mesangiocapillary glomerulonephritis: a long-term study of 40 cases.
      including one recent US series of 18 adults and 14 children in which 39% of adults were older than age 60 at diagnosis.
      • Nasr S.H.
      • Valeri A.M.
      • Appel G.B.
      • Sherwinter J.
      • Stokes M.B.
      • Said S.M.
      • et al.
      Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.
      Although this study and several others
      • Little M.A.
      • Dupont P.
      • Campbell E.
      • Dorman A.
      • Walshe J.J.
      Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk.
      • Bohle A.
      • Gärtner H.V.
      • Fischbach H.
      • Bock K.D.
      • Edel H.H.
      • Frotscher U.
      • et al.
      The morphological and clinical features of membranoproliferative glomerulonephritis in adults.
      • Klein M.
      • Poucell S.
      • Arbus G.S.
      • McGraw M.
      • Rance C.P.
      • Yoon S.J.
      • et al.
      Characteristics of a benign subtype of dense deposit disease: comparison with the progressive form of this disease.
      • Bennett W.M.
      • Fassett R.G.
      • Walker R.G.
      • Fairley K.F.
      • d'Apice A.J.
      • Kincaid-Smith P.
      Mesangiocapillary glomerulonephritis type II (dense-deposit disease): clinical features of progressive disease.
      found that DDD was almost twice as common in females as males, some have found the opposite,
      • Antoine B.
      • Faye C.
      The clinical course associated with dense deposits in the kidney basement membranes.
      • Park S.J.
      • Kim Y.J.
      • Ha T.S.
      • Lim B.J.
      • Jeong H.J.
      • Park Y.H.
      • et al.
      Dense deposit disease in Korean children: a multicenter clinicopathologic study.
      whilst the majority of studies have found no differences between males and females with DDD
      • Walker P.D.
      • Ferrario F.
      • Joh K.
      • Bonsib S.M.
      Dense deposit disease is not a membranoproliferative glomerulonephritis.
      • Wang J.
      • Tang Z.
      • Luo C.
      • Hu Y.
      • Zeng C.
      • Chen H.
      • et al.
      Clinical and pathological features of dense deposit disease in Chinese patients.
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      • Galle P.
      • Mahieu P.
      Electron dense alteration of kidney basement membranes. A renal lesion specific of a systemic disease.
      • Lu D.F.
      • Moon M.
      • Lanning L.D.
      • McCarthy A.M.
      • Smith R.J.
      Clinical features and outcomes of 98 children and adults with dense deposit disease.
      • Habib R.
      • Gubler M.C.
      • Loirat C.
      • Maïz H.B.
      • Levy M.
      Dense deposit disease: a variant of membranoproliferative glomerulonephritis.
      • Vargas R.
      • Thomson K.J.
      • Wilson D.
      • Cameron J.S.
      • Turner D.R.
      • Gill D.
      • et al.
      Mesangiocapillary glomerulonephritis with dense "deposits" in the basement membranes of the kidney.
      • Davis A.E.
      • Schneeberger E.E.
      • Grupe W.E.
      • McCluskey R.T.
      Membranoproliferative glomerulonephritis (MPGN type I) and dense deposit disease (DDD) in children.
      • Kashtan C.E.
      • Burke B.
      • Burch G.
      • Gustav Fisker S.
      • Kim Y.
      Dense intramembranous deposit disease: a clinical comparison of histological subtypes.
      or C3GN.
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      • Sethi S.
      • Fervenza F.C.
      • Zhang Y.
      • Zand L.
      • Vrana J.A.
      • Nasr S.H.
      • et al.
      C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.
      Native renal manifestations of C3 glomerulopathy are diverse and nonspecific, with hypertension, hematuria, proteinuria (with or without nephrotic syndrome), and renal failure all reported. Most studies have found no difference in presenting features between DDD and MPGN type 1.
      • Donadio Jr, J.V.
      • Slack T.K.
      • Holley K.E.
      • Ilstrup D.M.
      Idiopathic membranoproliferative (mesangiocapillary) glomerulonephritis: a clinicopathologic study.
      • Cameron J.S.
      • Turner D.R.
      • Heaton J.
      • Williams D.G.
      • Ogg C.S.
      • Chantler C.
      • et al.
      Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis.
      • Bohle A.
      • Gärtner H.V.
      • Fischbach H.
      • Bock K.D.
      • Edel H.H.
      • Frotscher U.
      • et al.
      The morphological and clinical features of membranoproliferative glomerulonephritis in adults.
      • Habib R.
      • Gubler M.C.
      • Loirat C.
      • Maïz H.B.
      • Levy M.
      Dense deposit disease: a variant of membranoproliferative glomerulonephritis.
      • Davis A.E.
      • Schneeberger E.E.
      • Grupe W.E.
      • McCluskey R.T.
      Membranoproliferative glomerulonephritis (MPGN type I) and dense deposit disease (DDD) in children.
      However, nephrotic syndrome was approximately twice as common in MPGN type 1 as either DDD or C3GN in the recently updated French C3 glomerulopathy series.
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      In CFHR5 nephropathy, persistent microscopic hematuria with or without episodes of synpharyngitic macroscopic hematuria (clinically identical to those seen in IgA nephropathy
      • Berger J.
      • Hinglais N.
      Les dépôts intercapillaires d'IgA-IgG.
      ) is the usual presentation. Identical features occasionally have been reported in DDD patients,
      • Bennett W.M.
      • Fassett R.G.
      • Walker R.G.
      • Fairley K.F.
      • d'Apice A.J.
      • Kincaid-Smith P.
      Mesangiocapillary glomerulonephritis type II (dense-deposit disease): clinical features of progressive disease.
      • Levy M.
      • Halbwachs-Mecarelli L.
      • Gubler M.C.
      • Kohout G.
      • Bensenouci A.
      • Niaudet P.
      • et al.
      H deficiency in two brothers with atypical dense intramembranous deposit disease.
      in whom the clinical and histologic overlap with acute postinfectious GN suggests that intercurrent infection is important in renal injury when AP dysregulation is present. Thus, symptoms of respiratory tract infection preceding renal symptoms have been described in children (not usually adults) with DDD,
      • Nasr S.H.
      • Valeri A.M.
      • Appel G.B.
      • Sherwinter J.
      • Stokes M.B.
      • Said S.M.
      • et al.
      Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.
      • Wang J.
      • Tang Z.
      • Luo C.
      • Hu Y.
      • Zeng C.
      • Chen H.
      • et al.
      Clinical and pathological features of dense deposit disease in Chinese patients.
      • Sethi S.
      • Fervenza F.C.
      • Zhang Y.
      • Nasr S.H.
      • Leung N.
      • Vrana J.
      • et al.
      Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement.
      • Antoine B.
      • Faye C.
      The clinical course associated with dense deposits in the kidney basement membranes.
      • Habib R.
      • Gubler M.C.
      • Loirat C.
      • Maïz H.B.
      • Levy M.
      Dense deposit disease: a variant of membranoproliferative glomerulonephritis.
      • Vargas R.
      • Thomson K.J.
      • Wilson D.
      • Cameron J.S.
      • Turner D.R.
      • Gill D.
      • et al.
      Mesangiocapillary glomerulonephritis with dense "deposits" in the basement membranes of the kidney.
      • Davis A.E.
      • Schneeberger E.E.
      • Grupe W.E.
      • McCluskey R.T.
      Membranoproliferative glomerulonephritis (MPGN type I) and dense deposit disease (DDD) in children.
      • Kashtan C.E.
      • Burke B.
      • Burch G.
      • Gustav Fisker S.
      • Kim Y.
      Dense intramembranous deposit disease: a clinical comparison of histological subtypes.
      • Lamb V.
      • Tisher C.C.
      • McCoy R.C.
      • Robinson R.R.
      Membranoproliferative glomerulonephritis with dense intramembranous alterations. A clinicopathologic study.
      • Jenis E.H.
      • Sandler P.
      • Hill G.S.
      • Knieser M.R.
      • Jensen G.E.
      • Roskes S.D.
      Glomerulonephritis with basement membrane dense deposits.
      sometimes in association with increased anti–streptolysin O titers.
      • Sethi S.
      • Fervenza F.C.
      • Zhang Y.
      • Nasr S.H.
      • Leung N.
      • Vrana J.
      • et al.
      Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement.
      • Habib R.
      • Gubler M.C.
      • Loirat C.
      • Maïz H.B.
      • Levy M.
      Dense deposit disease: a variant of membranoproliferative glomerulonephritis.
      • Kashtan C.E.
      • Burke B.
      • Burch G.
      • Gustav Fisker S.
      • Kim Y.
      Dense intramembranous deposit disease: a clinical comparison of histological subtypes.
      • Jenis E.H.
      • Sandler P.
      • Hill G.S.
      • Knieser M.R.
      • Jensen G.E.
      • Roskes S.D.
      Glomerulonephritis with basement membrane dense deposits.
      Nonrenal manifestations of DDD include ocular drusen, acquired partial lipodystrophy (PLD), type 1 diabetes mellitus, and monoclonal gammopathy of undetermined significance (MGUS). Ocular drusen are lipoproteinaceous deposits of complement-containing debris between the basal surface of the retinal pigment endothelium and Bruch’s membrane. The clinical association of ocular drusen with DDD was first reported in 1989,
      • Duvall-Young J.
      • MacDonald M.K.
      • McKechnie N.M.
      Fundus changes in (type II) mesangiocapillary glomerulonephritis simulating drusen: a histopathological report.
      and appears to be related to structural and functional similarities between Bruch’s membrane, a multilaminar extracellular matrix that separates the retina from the blood vessels in the choroid, and the GBM. Ocular drusen are also a manifestation of age-related macular degeneration (AMD),
      • Mullins R.F.
      • Aptsiauri N.
      • Hageman G.S.
      Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis.
      the leading cause of blindness in the industrialized world, for which a number of shared genetic risk factors with DDD are discussed later. However, unlike AMD, drusen in patients with DDD are said to occur at a young age and to be associated with only a modest risk of progressive visual loss.
      • Appel G.B.
      • Cook H.T.
      • Hageman G.
      • Jennette J.C.
      • Kashgarian M.
      • Kirschfink M.
      • et al.
      Membranoproliferative glomerulonephritis type II (dense deposit disease): an update.
      In the recent therapeutic trial of eculizumab in DDD and C3GN, among several patients identified as having ocular drusen, one patient had C3GN.
      • Bomback A.S.
      • Smith R.J.
      • Barile G.R.
      • Zhang Y.
      • Heher E.C.
      • Herlitz L.
      • et al.
      Eculizumab for dense deposit disease and C3 glomerulonephritis.
      PLD involves loss of subcutaneous fat from the face and upper body. An association with GN was first noted in 1958.
      • Gellis S.
      • Green S.
      • Walker D.
      Chronic renal disease in children.
      Early reports of PLD in patients with DDD
      • Eisinger A.J.
      • Shortland J.R.
      • Moorhead P.J.
      Renal disease in partial lipodystrophy.
      and C3NeF-associated MPGN (without EM)
      • Williams D.G.
      • Scopes J.W.
      • Peters D.K.
      Hypocomplementaemic membranoproliferative glomerulonephritis and nephrotic syndrome associated with partial lipodystrophy of the face and trunk.
      were followed by several MPGN cohorts in which PLD was associated specifically with DDD.
      • Cameron J.S.
      • Turner D.R.
      • Heaton J.
      • Williams D.G.
      • Ogg C.S.
      • Chantler C.
      • et al.
      Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis.
      • Swainson C.P.
      • Robson J.S.
      • Thomson D.
      • MacDonald M.K.
      Mesangiocapillary glomerulonephritis: a long-term study of 40 cases.
      • Habib R.
      • Gubler M.C.
      • Loirat C.
      • Maïz H.B.
      • Levy M.
      Dense deposit disease: a variant of membranoproliferative glomerulonephritis.
      In the updated French C3 glomerulopathy series, PLD was noted only in the DDD group,
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      affecting 17% of DDD patients (versus <5% in other recent DDD cohorts
      • Smith R.J.
      • Harris C.L.
      • Pickering M.C.
      Dense deposit disease.
      • Nasr S.H.
      • Satoskar A.
      • Markowitz G.S.
      • Valeri A.M.
      • Appel G.B.
      • Stokes M.B.
      • et al.
      Proliferative glomerulonephritis with monoclonal IgG deposits.
      ). However, in an early PLD series comprising six patients with MPGN (all having C3NeF and low serum C3 levels), one patient had only subendothelial deposits on EM.
      • Sissons J.G.
      • West R.J.
      • Fallows J.
      • Williams D.G.
      • Boucher B.J.
      • Amos N.
      • et al.
      The complement abnormalities of lipodystrophy.
      Moreover, the Necker hospital group reported two patients with PLD and MPGN in whom IF was positive for both C3 and IgG.
      • Hamza M.
      • Levy M.
      • Broyer M.
      • Habib R.
      Deux cas de glomérulo-néphrite membrano-proliférative avec lipodystrophie partielle de type facio-tronculaire.
      In a 2004 literature review of PLD, MPGN was the most common associated renal lesion, but only slightly more than half of MPGN cases were shown to be DDD, with MPGN types 1/3 also represented.
      • Misra A.
      • Peethambaram A.
      • Garg A.
      Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature.
      In the majority of cases of PLD, including those associated with low serum C3 levels, renal disease was not found.
      • Misra A.
      • Peethambaram A.
      • Garg A.
      Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature.
      A significantly increased risk of diabetes mellitus type 1 was reported in patients and families with DDD in a US questionnaire-based study of 98 patients (although ascertainment bias cannot be excluded).
      • Vargas R.
      • Thomson K.J.
      • Wilson D.
      • Cameron J.S.
      • Turner D.R.
      • Gill D.
      • et al.
      Mesangiocapillary glomerulonephritis with dense "deposits" in the basement membranes of the kidney.
      It has been suggested that MGUS is associated with DDD
      • Nasr S.H.
      • Valeri A.M.
      • Appel G.B.
      • Sherwinter J.
      • Stokes M.B.
      • Said S.M.
      • et al.
      Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.
      • Sepandj F.
      • Trillo A.
      Dense deposit disease in association with monoclonal gammopathy of unknown significance.
      • Sethi S.
      • Sukov W.R.
      • Zhang Y.
      • Fervenza F.C.
      • Lager D.J.
      • Miller D.V.
      • et al.
      Dense deposit disease associated with monoclonal gammopathy of undetermined significance.
      and C3GN,
      • Bridoux F.
      • Desport E.
      • Frémeaux-Bacchi V.
      • Chong C.F.
      • Gombert J.M.
      • Lacombe C.
      • et al.
      Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association?.
      • Zand L.
      • Kattah A.
      • Fervenza F.C.
      • Smith R.J.
      • Nasr S.H.
      • Zhang Y.
      • et al.
      C3 glomerulonephritis associated with monoclonal gammopathy: a case series.
      and that it may confer a poor renal prognosis.

      Prognosis

      Progression to end-stage kidney disease (ESKD), despite treatment, is said to occur in approximately half of patients with a diagnosis of DDD of 10 or more years.
      • Swainson C.P.
      • Robson J.S.
      • Thomson D.
      • MacDonald M.K.
      Mesangiocapillary glomerulonephritis: a long-term study of 40 cases.
      • Bennett W.M.
      • Fassett R.G.
      • Walker R.G.
      • Fairley K.F.
      • d'Apice A.J.
      • Kincaid-Smith P.
      Mesangiocapillary glomerulonephritis type II (dense-deposit disease): clinical features of progressive disease.
      • Appel G.B.
      • Cook H.T.
      • Hageman G.
      • Jennette J.C.
      • Kashgarian M.
      • Kirschfink M.
      • et al.
      Membranoproliferative glomerulonephritis type II (dense deposit disease): an update.
      • Schwertz R.
      • de Jong R.
      • Gretz N.
      • Kirschfink M.
      • Anders D.
      • Schärer K.
      Outcome of idiopathic membranoproliferative glomerulonephritis in children.
      • Smith R.J.
      • Alexander J.
      • Barlow P.N.
      • Botto M.
      • Cassavant T.L.
      • Cook H.T.
      • et al.
      New approaches to the treatment of dense deposit disease.
      In the recently updated French C3 glomerulopathy series, overall 10-year progression to ESKD was 36.5% (with a mean follow-up period of 11 years).
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      No significant difference was seen between the three diagnostic categories (DDD, C3GN, and MPGN type 1). This is consistent with the finding in earlier MPGN cohort studies that DDD was not more likely than other forms of MPGN to progress to ESKD.
      • Habib R.
      • Kleinknecht C.
      • Gubler M.C.
      • Maïz H.B.
      Idiopathic membranoproliferative glomerulonephritis. Morphology and natural history.
      • Cameron J.S.
      • Turner D.R.
      • Heaton J.
      • Williams D.G.
      • Ogg C.S.
      • Chantler C.
      • et al.
      Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis.
      • Swainson C.P.
      • Robson J.S.
      • Thomson D.
      • MacDonald M.K.
      Mesangiocapillary glomerulonephritis: a long-term study of 40 cases.
      • Davis A.E.
      • Schneeberger E.E.
      • Grupe W.E.
      • McCluskey R.T.
      Membranoproliferative glomerulonephritis (MPGN type I) and dense deposit disease (DDD) in children.
      • Cansick J.C.
      • Lennon R.
      • Cummins C.L.
      • Howie A.J.
      • McGraw M.E.
      • Saleem M.A.
      • et al.
      Prognosis, treatment and outcome of childhood mesangiocapillary (membranoproliferative) glomerulonephritis.
      • di Belgiojoso B.
      • Tarantino A.
      • Colasanti G.
      • Bazzi C.
      • Guerra L.
      • Durante A.
      The prognostic value of some clinical and histological parameters in membranoproliferative glomerulonephritis (MPGN): report of 112 cases.
      • Somers M.
      • Kertesz S.
      • Rosen S.
      • Herrin J.
      • Colvin R.
      • Palacios de Carreta N.
      • et al.
      Non-nephrotic children with membranoproliferative glomerulonephritis: are steroids indicated?.
      Other series found that an apparent increase in ESKD rates probably was confounded by a higher incidence of crescents
      • Little M.A.
      • Dupont P.
      • Campbell E.
      • Dorman A.
      • Walshe J.J.
      Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk.
      • Habib R.
      • Gubler M.C.
      • Loirat C.
      • Maïz H.B.
      • Levy M.
      Dense deposit disease: a variant of membranoproliferative glomerulonephritis.
      or reduced GFR
      • Schwertz R.
      • de Jong R.
      • Gretz N.
      • Kirschfink M.
      • Anders D.
      • Schärer K.
      Outcome of idiopathic membranoproliferative glomerulonephritis in children.
      at diagnosis in the DDD versus non-DDD patient groups.
      The impact of clinical or histologic variables on outcomes of C3 glomerulopathy has been assessed in numerous retrospective cohort studies. In the two most recent DDD cohorts, reduced GFR at diagnosis was associated significantly on multivariate analysis with progression to ESKD.
      • Nasr S.H.
      • Valeri A.M.
      • Appel G.B.
      • Sherwinter J.
      • Stokes M.B.
      • Said S.M.
      • et al.
      Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      In CFHR5 nephropathy, in which progressive disease is characterized by hypertension, proteinuria, and chronic renal failure, ESKD has been reported in 18 of 91 carriers (or 20%) of the heterozygous CFHR5 gene mutation. Of these, 14 were men and 4 were women, a difference that remains unexplained. No other features have been shown consistently to correlate with disease outcomes in DDD or other forms of C3 glomerulopathy. This is partly because of the limited number of end points that can be assessed in mostly small cohorts. In the updated French C3 glomerulopathy cohort,
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      adults with DDD had significantly reduced renal survival compared with children with DDD, adults with C3GN, and adults with MPGN type 1. However, the DDD adult subgroup comprised only 11 patients, and because other differences between these subgroups were not assessed it is difficult to determine if this was a robust conclusion. For some variables, including the presence of crescents on the diagnostic biopsy specimen (found to predict a rapid progression to ESKD in some DDD cohorts
      • Habib R.
      • Gubler M.C.
      • Loirat C.
      • Maïz H.B.
      • Levy M.
      Dense deposit disease: a variant of membranoproliferative glomerulonephritis.
      • Miller M.N.
      • Baumal R.
      • Poucell S.
      • Steele B.T.
      Incidence and prognostic importance of glomerular crescents in renal diseases of childhood.
      but not others
      • Nasr S.H.
      • Valeri A.M.
      • Appel G.B.
      • Sherwinter J.
      • Stokes M.B.
      • Said S.M.
      • et al.
      Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.
      • Cameron J.S.
      • Turner D.R.
      • Heaton J.
      • Williams D.G.
      • Ogg C.S.
      • Chantler C.
      • et al.
      Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis.
      • Antoine B.
      • Faye C.
      The clinical course associated with dense deposits in the kidney basement membranes.
      ), it now seems especially clear that prognostic value cannot be assessed adequately through retrospective cohort analyses. This is exemplified by the US DDD cohort study in which it was suggested that the reason crescents did not correlate with outcomes may have been the increased use of immunosuppressants in such patients.
      • Nasr S.H.
      • Valeri A.M.
      • Appel G.B.
      • Sherwinter J.
      • Stokes M.B.
      • Said S.M.
      • et al.
      Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.

      Pathogenesis

      C3 Nephritic Factors

      Reduced serum C3 (but not C4) is consistent with AP dysregulation, but is neither sensitive nor specific for the diagnosis of DDD/C3GN. In recent cohort studies, isolated low C3 level was found in only a proportion of patients with DDD
      • Nasr S.H.
      • Valeri A.M.
      • Appel G.B.
      • Sherwinter J.
      • Stokes M.B.
      • Said S.M.
      • et al.
      Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      and C3GN.
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      • Sethi S.
      • Fervenza F.C.
      • Zhang Y.
      • Zand L.
      • Vrana J.A.
      • Nasr S.H.
      • et al.
      C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.
      C3NeF, first described in a patient with “persistent hypocomplementemic glomerulonephritis,”
      • Spitzer R.E.
      • Vallota E.H.
      • Forristal J.
      • Sudora E.
      • Stitzel A.
      • Davis N.C.
      • et al.
      Serum C'3 lytic system in patients with glomerulonephritis.
      is an autoantibody that binds to a neoepitope on C3bBb, the C3 convertase of the AP, stabilizing it against complement factor H (Cfh)-mediated decay and prolonging its C3-cleaving action.
      • Daha M.R.
      • Fearon D.T.
      • Austen K.F.
      C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase.
      A second type of C3NeF was found to display slower C3 and C5 activation
      • Mollnes T.E.
      • Ng Y.C.
      • Peters D.K.
      • Lea T.
      • Tschopp J.
      • Harboe M.
      Effect of nephritic factor on C3 and on the terminal pathway of complement in vivo and in vitro.
      and dependence on properdin for convertase stabilization.
      • Clardy C.W.
      • Forristal J.
      • Strife C.F.
      • West C.D.
      A properdin dependent nephritic factor slowly activating C3, C5, and C9 in membranoproliferative glomerulonephritis, types I and III.
      It has been reported in very small series that properdin-dependent C3NeFs are more characteristic of MPGN types 1
      • Clardy C.W.
      • Forristal J.
      • Strife C.F.
      • West C.D.
      A properdin dependent nephritic factor slowly activating C3, C5, and C9 in membranoproliferative glomerulonephritis, types I and III.
      • Tanuma Y.
      • Ohi H.
      • Hatano M.
      Two types of C3 nephritic factor: properdin-dependent C3NeF and properdin-independent C3NeF.
      and 3,
      • Clardy C.W.
      • Forristal J.
      • Strife C.F.
      • West C.D.
      A properdin dependent nephritic factor slowly activating C3, C5, and C9 in membranoproliferative glomerulonephritis, types I and III.
      whereas properdin-independent C3NeFs are found more often in DDD and PLD.
      • Tanuma Y.
      • Ohi H.
      • Hatano M.
      Two types of C3 nephritic factor: properdin-dependent C3NeF and properdin-independent C3NeF.
      In the updated French C3 glomerulopathy cohort,
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      C3NeFs were significantly more common in patients with DDD than C3GN or MPGN type 1 (consistent with earlier studies
      • Cameron J.S.
      • Turner D.R.
      • Heaton J.
      • Williams D.G.
      • Ogg C.S.
      • Chantler C.
      • et al.
      Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis.
      • Swainson C.P.
      • Robson J.S.
      • Thomson D.
      • MacDonald M.K.
      Mesangiocapillary glomerulonephritis: a long-term study of 40 cases.
      • Schwertz R.
      • Rother U.
      • Anders D.
      • Gretz N.
      • Schärer K.
      • Kirschfink M.
      Complement analysis in children with idiopathic membranoproliferative glomerulonephritis: a long-term follow-up.
      ). Patients with C3NeFs also had generally lower C3 levels (although C3 was normal in ~40% of patients with C3NeF). Here, as in most DDD/C3GN studies, serum C3 levels and the presence of C3NeF did not correlate with disease outcomes. The identification of C3NeFs in patients with other forms of GN and in healthy individuals (discussed in one recent study
      • Zhang Y.
      • Meyer N.C.
      • Wang K.
      • Nishimura C.
      • Frees K.
      • Jones M.
      • et al.
      Causes of alternative pathway dysregulation in dense deposit disease.
      ) underlines a lack of specificity. In CFHR5 nephropathy, C3 levels typically are normal and C3NeF is absent.
      • Gale D.P.
      • Goicoechea de Jorge E.
      • Cook H.T.
      • Martínez-Barricarte R.
      • Hadjisavvas A.
      • McLean A.G.
      • et al.
      Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.
      Autoantibodies that bind to native factor B (Cfb) and stabilize the AP C3 convertase
      • Strobel S.
      • Zimmering M.
      • Papp K.
      • Prechl J.
      • Józsi M.
      Anti-factor B autoantibody in dense deposit disease.
      or target both Cfb and C3b
      • Chen Q.
      • Müller D.
      • Rudolph B.
      • Hartmann A.
      • Kuwertz-Bröking E.
      • Wu K.
      • et al.
      Combined C3b and factor B autoantibodies and MPGN type II.
      also have been described in patients with DDD. An early report showed that circulating monoclonal Ig λ light chain dimers were able to activate the AP.
      • Meri S.
      • Koistinen V.
      • Miettinen A.
      • Törnroth T.
      • Seppälä I.J.
      Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis.
      The λ light chain dimers were found to bind short consensus repeat (SCR) 3 on the Cfh molecule, blocking one of its C3b interaction sites.
      • Jokiranta T.S.
      • Solomon A.
      • Pangburn M.K.
      • Zipfel P.F.
      • Meri S.
      Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H.
      Subsequently, anti-Cfh autoantibodies have been identified in patients with DDD
      • Sethi S.
      • Sukov W.R.
      • Zhang Y.
      • Fervenza F.C.
      • Lager D.J.
      • Miller D.V.
      • et al.
      Dense deposit disease associated with monoclonal gammopathy of undetermined significance.
      • Zhang Y.
      • Meyer N.C.
      • Wang K.
      • Nishimura C.
      • Frees K.
      • Jones M.
      • et al.
      Causes of alternative pathway dysregulation in dense deposit disease.
      • Goodship T.H.
      • Pappworth I.Y.
      • Toth T.
      • Denton M.
      • Houlberg K.
      • McCormick F.
      • et al.
      Factor H autoantibodies in membranoproliferative glomerulonephritis.
      and C3GN.
      • Sethi S.
      • Fervenza F.C.
      • Zhang Y.
      • Nasr S.H.
      • Leung N.
      • Vrana J.
      • et al.
      Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement.
      • Bridoux F.
      • Desport E.
      • Frémeaux-Bacchi V.
      • Chong C.F.
      • Gombert J.M.
      • Lacombe C.
      • et al.
      Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association?.

      Family Studies

      Renal biopsy data for a number of family studies in C3 glomerulopathy are shown in Table 1. These studies indicate a genetic basis for a small number of C3 glomerulopathy cases, although the genetic defect has been characterized and an underlying pathogenic mechanism proposed in only a handful of families. These include cases associated with homozygous Cfh deficiency or homozygous loss-of-function Cfh mutation, heterozygous gain-of-function C3 mutation, and CFHR mutations leading to enhanced Cfh deregulation (summarized later and in Figure 3). Two Algerian brothers of consanguineous parents were reported with severe Cfh deficiency and autosomal-recessive “atypical DDD” as shown on EM by discontinuous intramembranous deposits.
      • Levy M.
      • Halbwachs-Mecarelli L.
      • Gubler M.C.
      • Kohout G.
      • Bensenouci A.
      • Niaudet P.
      • et al.
      H deficiency in two brothers with atypical dense intramembranous deposit disease.
      Renal disease presented during infancy with intermittent macroscopic hematuria and infections (including pharyngitis) together with failure to thrive and developmental delay in the younger sibling. Both brothers were negative for C3NeF but had very low serum levels of C3, Cfb, properdin, and C5 with normal classic pathway components. A homozygous missense mutation in SCR 7 of the Cfh gene, causing a substitution of a cysteine with a serine residue, subsequently was identified in the elder brother.
      • Dragon-Durey M.A.
      • Frémeaux-Bacchi V.
      • Loirat C.
      • Blouin J.
      • Niaudet P.
      • Deschenes G.
      • et al.
      Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases.
      Both parents and two other children without renal disease had half-normal Cfh levels, consistent with heterozygosity. A young girl presenting with recurrent macroscopic hematuria and undetectable serum C3, Cfb, and Cfh was found to have C3GN with a mesangioproliferative pattern and predominant mesangial deposits on EM.
      • Rusai K.
      • Zaller V.
      • Szilagyi A.
      • Kain R.
      • Prohaszka Z.
      • Cook H.T.
      • et al.
      A rare case: childhood-onset C3 glomerulonephritis due to homozygous factor H deficiency.
      A homozygous missense mutation was detected on SCR 16 of Cfh that resulted in a cysteine to serine change. Both unaffected parents were heterozygous for the Cfh mutation and displayed low-normal Cfh levels, while an unaffected sister had two normal Cfh alleles and high-normal Cfh levels. Intriguingly, an earlier report concerned a patient with severe Cfh deficiency in association with type 3 collagen glomerulopathy
      • Vogt B.A.
      • Wyatt R.J.
      • Burke B.A.
      • Simonton S.C.
      • Kashtan C.E.
      Inherited factor H deficiency and collagen type III glomerulopathy.
      (more likely representing chronic thrombotic microangiopathy
      • Pickering M.C.
      • Cook H.T.
      Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals.
      ) in whom a different homozygous missense mutation was identified at the same site on SCR 16.
      • Ault B.H.
      • Schmidt B.Z.
      • Fowler N.L.
      • Kashtan C.E.
      • Ahmed A.E.
      • Vogt B.A.
      • et al.
      Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism.
      The substitution of a cysteine residue (in this case with a tyrosine) altered the secondary structure of the Cfh protein, resulting in its nonsecretion.
      • Schmidt B.Z.
      • Fowler N.L.
      • Hidvegi T.
      • Perlmutter D.H.
      • Colten H.R.
      Disruption of disulfide bonds is responsible for impaired secretion in human complement factor H deficiency.
      A young girl was reported with macroscopic hematuria, very low C3 and Cfh levels, and endocapillary GN with predominant glomerular C3.
      • Schejbel L.
      • Schmidt I.M.
      • Kirchhoff M.
      • Andersen C.B.
      • Marquart H.V.
      • Zipfel P.
      • et al.
      Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation.
      A homozygous missense mutation on SCR 2, causing an exchange of proline to serine, was apparently the result of paternal isodisomy. The patient also was homozygous for a risk haplotype for the membrane cofactor protein (MCP) gene (discussed later).
      • Wilson V.
      • Darlay R.
      • Wong W.
      • Wood K.M.
      • McFarlane J.
      • Schejbel L.
      • et al.
      Genotype/phenotype correlations in complement factor h deficiency arising from uniparental isodisomy.
      Table 1Renal Biopsy Data in Family Studies of C3 Glomerulopathy
      Figure thumbnail gr3
      Figure 3Disease mechanisms in C3 glomerulopathy, based on genetic defects identified in family studies. (A) Physiological regulation of C3 activation to C3b via the alternative pathway is mediated by Cfh. Competitive inhibition of Cfh by CFHR proteins is termed Cfh deregulation. (B) Homozygous deficiency or dysfunction of Cfh results in excessive C3 activation. (C) Hyperfunctional C3 produces excessive C3 activation despite normal Cfh activity. (D) Abnormal CFHR proteins enhance Cfh deregulation, leading to excessive C3 activation.
      Two young daughters of consanguineous Turkish parents had C3GN with low C3, positive C3NeF, and only slightly reduced serum Cfh levels.
      • Licht C.
      • Heinen S.
      • Józsi M.
      • Loschmann I.
      • Saunders R.E.
      • Perkins S.J.
      • et al.
      Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II).
      • Habbig S.
      • Mihatsch M.J.
      • Heinen S.
      • Beck B.
      • Emmel M.
      • Skerka C.
      • et al.
      C3 deposition glomerulopathy due to a functional factor H defect.
      A loss-of-function homozygous mutation in Cfh involving deletion of a single codon in SCR 4 was found to produce a circulating mutant Cfh protein with impaired binding to C3b, defective decay accelerating activity, and reduced factor I (Cfi) cofactor activity. Both patients also were homozygous for the DDD/AMD-associated Y402H Cfh polymorphism (discussed later). A mother and her twin adult sons had DDD in association with half-normal C3 and Cfb levels and normal Cfh levels.
      • Martínez-Barricarte R.
      • Heurich M.
      • Valdes-Cañedo F.
      • Vazquez-Martul E.
      • Torreira E.
      • Montes T.
      • et al.
      Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation.
      A gain-of-function heterozygous mutation of the C3 gene involving deletion of two codons was found to produce a hyperfunctional C3 protein. Mutant C3 was unable to be activated by the C3 convertase of the AP. However, after its conversion by proteases to C3b or by spontaneous hydrolysis of the internal thioester (C3 tickover) to C3(H2O), it formed a C3 convertase that was resistant to regulation by Cfh. This resulted in accelerated breakdown of wild-type C3 that appeared to be restricted to the fluid phase, because regulation in vitro by decay accelerating factor (DAF, a surface-expressed complement regulatory protein) was intact. Similarly, mutant C3b and C3(H2O) did not undergo Cfi-mediated proteolysis in the fluid phase (being dependent on Cfh cofactor activity), whereas proteolysis proceeded efficiently in the presence of MCP.
      In CFHR5 nephropathy, multiplex-ligation probe amplification enabled the identification of a novel heterozygous mutation in the CFHR5 gene involving internal duplication of the initial two N-terminal SCRs in two affected families originally from the Troodos region of Cyprus.
      • Gale D.P.
      • Goicoechea de Jorge E.
      • Cook H.T.
      • Martínez-Barricarte R.
      • Hadjisavvas A.
      • McLean A.G.
      • et al.
      Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.
      The finding of a common mutation in these families suggested a founder effect, and subsequently diagnostic polymerase chain reaction enabled the identification of numerous additional affected individuals and families from all over Cyprus (some with a previous diagnosis of MPGN type 1). A total of 91 carriers of the same heterozygous founder mutation from 16 apparently unrelated Greek-Cypriot families was later reported, with a disease penetrance of 90%.
      • Athanasiou Y.
      • Voskarides K.
      • Gale D.P.
      • Damianou L.
      • Patsias C.
      • Zavros M.
      • et al.
      Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.
      An Irish family was first reported with autosomal-dominant MPGN type 3
      • Neary J.
      • Dorman A.
      • Campbell E.
      • Keogan M.
      • Conlon P.
      Familial membranoproliferative glomerulonephritis type III.
      (now reclassified as C3 glomerulopathy) and linkage to the regulators of complement activation locus.
      • Neary J.J.
      • Conlon P.J.
      • Croke D.
      • Dorman A.
      • Keogan M.
      • Zhang F.Y.
      • et al.
      Linkage of a gene causing familial membranoproliferative glomerulonephritis type III to chromosome 1.
      A novel hybrid CFHR3-1 gene now has been identified encoding an abnormal CFHR3-1 protein in affected family members.
      • Malik T.H.
      • Lavin P.J.
      • Goicoechea de Jorge E.
      • Vernon K.A.
      • Rose K.L.
      • Patel M.P.
      • et al.
      A hybrid CFHR3-1 gene causes familial C3 glomerulopathy.

      Cfh Deregulation

      Until recently, the biological role of the five CFHR proteins has been unclear, although the presence of polymorphisms involving homozygous deletion of CFHR genes (most commonly ΔCFHR3/1)
      • Hageman G.S.
      • Hancox L.S.
      • Taiber A.J.
      • Gehrs K.M.
      • Anderson D.H.
      • Johnson L.V.
      • et al.
      Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications.
      in healthy populations suggested that the CFHR3 and CFHR1 proteins were nonessential. Recently, CFHR1, CFHR2, and CFHR5 have been shown to possess a common dimerization motif located within the highly conserved first two N-terminal SCRs of these particular CFHR proteins. It is now believed that, unlike Cfh, these CFHR proteins do not have any complement inhibiting actions in vivo. Rather, they compete with Cfh for binding to C3b, thereby enhancing C3 activation in a process termed Cfh deregulation.
      • Goicoechea de Jorge E.
      • Caesar J.J.
      • Malik T.H.
      • Patel M.
      • Colledge M.
      • Johnson S.
      • et al.
      Dimerization of complement factor H-related proteins modulates complement activation in vivo.
      Both dimerization and deregulation have implications for understanding how CFHR proteins mediate autosomal-dominant C3 glomerulopathy. In CFHR5 nephropathy, the mutation results in the duplication of the dimerization motif and enables generation of large complexes that have enhanced deregulation.
      • Goicoechea de Jorge E.
      • Caesar J.J.
      • Malik T.H.
      • Patel M.
      • Colledge M.
      • Johnson S.
      • et al.
      Dimerization of complement factor H-related proteins modulates complement activation in vivo.
      Enhanced deregulation also has been shown using serum containing the abnormal (hybrid) CFHR3-1 protein.
      • Goicoechea de Jorge E.
      • Caesar J.J.
      • Malik T.H.
      • Patel M.
      • Colledge M.
      • Johnson S.
      • et al.
      Dimerization of complement factor H-related proteins modulates complement activation in vivo.
      The current paradigm is that there is either continuous or intermittent (eg, during infection) activation of C3 along the GBM that is controlled by Cfh. In the presence of abnormal CFHR proteins, enhanced deregulation of Cfh enables C3 to accumulate along the GBM. This paradigm would predict that a lack of CFHR proteins (eg, through the common ΔCFHR3/1 allele) would enhance Cfh action and become a protective factor in C3 glomerulopathy or complement-mediated disease in general. It also may explain the protective effect of ΔCFHR3/1 in AMD
      • Hageman G.S.
      • Hancox L.S.
      • Taiber A.J.
      • Gehrs K.M.
      • Anderson D.H.
      • Johnson L.V.
      • et al.
      Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications.
      • Hughes A.E.
      • Orr N.
      • Esfandiary H.
      • Diaz-Torres M.
      • Goodship T.
      • Chakravarthy U.
      A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration.
      and IgA nephropathy.
      • Gharavi A.G.
      • Kiryluk K.
      • Choi M.
      • Li Y.
      • Hou P.
      • Xie J.
      • et al.
      Genome-wide association study identifies susceptibility loci for IgA nephropathy.
      Homozygous ΔCFHR3/1 was absent in one cohort of 68 DDD patients, despite a rate among healthy control subjects of 3%.
      • Smith R.J.
      • Harris C.L.
      • Pickering M.C.
      Dense deposit disease.

      Other Genetic Associations

      Additional genetic variations in complement proteins and/or regulators have been identified using a candidate gene approach in individuals and cohorts with C3 glomerulopathy. Most of those in whom a rare genetic variant has been found have a family history of disease (and hence a higher pretest probability of genetically determined susceptibility). The relatively poor yield of genetic screening to date in nonfamilial cases is exemplified by the French C3 glomerulopathy cohort, in which mutations in one of three genes (Cfh, Cfi, and MCP) was reported in only 18% of all patients screened.
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      Cfh mutations were the most common, occurring in 9 of 16 individuals with a family history, but in only 8 nonfamilial cases. Another remarkable finding in this study was of no overall difference in the proportion of patients with DDD, C3GN, and MPGN type 1 in whom mutations affecting complement regulatory proteins were found. Thus, patients with homozygous Cfh mutations were identified in DDD (as outlined earlier), C3GN (patient 3
      • Servais A.
      • Noël L.H.
      • Dragon-Durey M.A.
      • Gubler M.C.
      • Remy P.
      • Buob D.
      • et al.
      Heterogeneous pattern of renal disease associated with homozygous factor H deficiency.
      ), and MPGN type 1 (patient 2
      • Servais A.
      • Noël L.H.
      • Dragon-Durey M.A.
      • Gubler M.C.
      • Remy P.
      • Buob D.
      • et al.
      Heterogeneous pattern of renal disease associated with homozygous factor H deficiency.
      and case 1
      • Vaziri-Sani F.
      • Holmberg L.
      • Sjoholm A.G.
      • Kristoffersson A.C.
      • Manea M.
      • Frémeaux-Bacchi V.
      • et al.
      Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome.
      ). However, the bulk of mutations identified in the French cohort were heterozygous. Two patients treated with eculizumab in the recent therapeutic trial also had heterozygous mutations affecting Cfh and MCP.
      • Bomback A.S.
      • Smith R.J.
      • Barile G.R.
      • Zhang Y.
      • Heher E.C.
      • Herlitz L.
      • et al.
      Eculizumab for dense deposit disease and C3 glomerulonephritis.
      Unlike homozygous Cfh deficiency, for which an animal model exists (discussed later), the functional basis of heterozygous mutations in C3 glomerulopathy remains unclear, notwithstanding that some have shown a correlation with AP dysregulation in patients with aHUS. Of note, homozygous Cfi deficiency, first reported in a patient with extremely low C3 and increased susceptibility to infection,
      • Alper C.A.
      • Abramson N.
      • Johnston Jr, R.B.
      • Jandl J.H.
      • Rosen F.S.
      Increased susceptibility to infection associated with abnormalities of complement-mediated functions and of the third component of complement (C3).
      has not been reported in association with C3 glomerulopathy.
      Screening of patient cohorts, followed by comparison with control populations, also identified common allelic variants that may modify risk of C3 glomerulopathy. Multiple genetic variants potentially conferring either increased risk or protection for C3 glomerulopathy and/or other complement-related phenotypes are said to define an individual’s complotype. Thus, single-nucleotide polymorphisms (SNPs) in the Cfh and C3 genes and a deletional copy number variation in C4A are associated with increased risk of DDD, whereas an SNP in CFHR5 is protective.
      • Abrera-Abeleda M.A.
      • Nishimura C.
      • Frees K.
      • Jones M.
      • Maga T.
      • Katz L.M.
      • et al.
      Allelic variants of complement genes associated with dense deposit disease.
      An SNP in MCP also is associated with an increased risk of C3GN and MPGN type 1.
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      At-risk haplotypes combining multiple SNPs in Cfh
      • Pickering M.C.
      • Goicoechea de Jorge E.
      • Martínez-Barricarte R.
      • Recalde S.
      • Garcia-Layana A.
      • Rose K.L.
      • et al.
      Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains.
      and C3
      • Abrera-Abeleda M.A.
      • Nishimura C.
      • Frees K.
      • Jones M.
      • Maga T.
      • Katz L.M.
      • et al.
      Allelic variants of complement genes associated with dense deposit disease.
      have been delineated for DDD, together with a protective Cfh haplotype.
      • Pickering M.C.
      • Goicoechea de Jorge E.
      • Martínez-Barricarte R.
      • Recalde S.
      • Garcia-Layana A.
      • Rose K.L.
      • et al.
      Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains.
      An at-risk MCP haplotype for C3GN and MPGN type 1 and a protective MCP haplotype for DDD and C3GN also have been reported.
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      In some, but not all, cases, functional studies showing AP dysregulation have provided evidence in support of the genetic association.
      • Heurich M.
      • Martínez-Barricarte R.
      • Francis N.J.
      • Roberts D.L.
      • Rodríguez de Córdoba S.
      • Morgan B.P.
      • et al.
      Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk.
      In AMD, approximately 50% of the population-attributable risk is accounted for by common polymorphisms in the Cfh gene. Several AMD-associated Cfh sequence variants have been shown to confer a common susceptibility to DDD.
      • Hageman G.S.
      • Anderson D.H.
      • Johnson L.V.
      • Hancox L.S.
      • Taiber A.J.
      • Hardisty L.I.
      • et al.
      A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.
      One important example is the Y402H substitution of a histidine (H) for a tyrosine (Y) residue on SCR 7, strongly associated with both AMD
      • Pickering M.C.
      • Goicoechea de Jorge E.
      • Martínez-Barricarte R.
      • Recalde S.
      • Garcia-Layana A.
      • Rose K.L.
      • et al.
      Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains.
      • Hageman G.S.
      • Anderson D.H.
      • Johnson L.V.
      • Hancox L.S.
      • Taiber A.J.
      • Hardisty L.I.
      • et al.
      A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.
      and DDD
      • Pickering M.C.
      • Goicoechea de Jorge E.
      • Martínez-Barricarte R.
      • Recalde S.
      • Garcia-Layana A.
      • Rose K.L.
      • et al.
      Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains.
      in Caucasian but not Asian populations. Functional studies have indicated that Y402H affects differential binding of Cfh to glycosaminoglycans within Bruch’s membrane and the glomerulus.
      • Clark S.J.
      • Ridge L.A.
      • Herbert A.P.
      • Hakobyan S.
      • Mulloy B.
      • Lennon R.
      • et al.
      Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions.
      An illustrative case relates to a 56-year-old man in whom ESKD developed as a result of DDD (without diagnostic EM), followed by new-onset AMD, causing eventual blindness.
      • Montes T.
      • Goicoechea de Jorge E.
      • Ramos R.
      • Gomà M.
      • Pujol O.
      • Sánchez-Corral P.
      • et al.
      Genetic deficiency of complement factor H in a patient with age-related macular degeneration and membranoproliferative glomerulonephritis.
      In this individual, genetic susceptibility to AMD and DDD derived from a heterozygous Cfh mutation in SCR 7, a homozygous risk haplotype comprising the H402 variant for SCR 7, and several other AMD risk factors.

      Animal Models

      Pigs
      • Hegasy G.A.
      • Manuelian T.
      • Høgåsen K.
      • Jansen J.H.
      • Zipfel P.F.
      The molecular basis for hereditary porcine membranoproliferative glomerulonephritis type II: point mutations in the factor H coding sequence block protein secretion.
      and mice
      • Pickering M.C.
      • Cook H.T.
      • Warren J.
      • Bygrave A.E.
      • Moss J.
      • Walport M.J.
      • et al.
      Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H.
      • Pickering M.C.
      • Warren J.
      • Rose K.L.
      • Carlucci F.
      • Wang Y.
      • Walport M.J.
      • et al.
      Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice.
      • Rose K.L.
      • Paixão-Cavalcante D.
      • Fish J.
      • Manderson A.P.
      • Malik T.H.
      • Bygrave A.E.
      • et al.
      Factor I is required for the development of membranoproliferative glomerulonephritis in factor H-deficient mice.
      • Paixão-Cavalcante D.
      • Hanson S.
      • Botto M.
      • Cook H.T.
      • Pickering M.C.
      Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase.
      • Fakhouri F.
      • Goicoechea de Jorge E.
      • Brune F.
      • Azam P.
      • Cook H.T.
      • Pickering M.C.
      Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice.
      with homozygous Cfh deficiency have provided an important experimental model of DDD. In Norwegian Yorkshire piglets (now extinct), a lethal Cfh mutation occurred spontaneously and was associated with severe renal disease described as porcine MPGN type 2. Gene-targeted Cfh-deficient mice show AP dysregulation with extremely low plasma C3 levels.
      • Pickering M.C.
      • Cook H.T.
      • Warren J.
      • Bygrave A.E.
      • Moss J.
      • Walport M.J.
      • et al.
      Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H.
      Cfh−/− mice develop albuminuria and MPGN, with significantly reduced survival compared with wild-type mice. In both models glomerular C3 without Ig is seen at an early stage and precedes the appearance on EM of capillary wall dense deposits. These electron-dense deposits are initially subendothelial rather than intramembranous, and show positive staining for C3 using immunoelectron microscopy. The absence of extraglomerular C3 is reminiscent of “atypical DDD,” as described in the family study of homozygous Cfh deficiency.
      • Levy M.
      • Halbwachs-Mecarelli L.
      • Gubler M.C.
      • Kohout G.
      • Bensenouci A.
      • Niaudet P.
      • et al.
      H deficiency in two brothers with atypical dense intramembranous deposit disease.
      Cfh−/− mice crossed with Cfb-deficient mice do not show low plasma C3 levels or glomerular changes, indicating that uncontrolled C3 activation via the AP is critical to renal pathogenesis. Injection into Cfh−/− mice of a single dose of purified murine
      • Paixão-Cavalcante D.
      • Hanson S.
      • Botto M.
      • Cook H.T.
      • Pickering M.C.
      Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase.
      or human
      • Fakhouri F.
      • Goicoechea de Jorge E.
      • Brune F.
      • Azam P.
      • Cook H.T.
      • Pickering M.C.
      Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice.
      Cfh restores plasma C3 levels to normal at 24 hours, accompanied by the resolution on IF of GBM C3 staining and the appearance of mesangial C3. In affected piglets, weekly plasma infusions containing Cfh also reduced the severity of GN and improved survival.
      • Jansen J.H.
      • Høgåsen K.
      • Harboe M.
      • Hovig T.
      In situ complement activation in porcine membranoproliferative glomerulonephritis type II.
      The role of C5 in this phenotype was studied by crossing Cfh−/− mice with those lacking C5.
      • Pickering M.C.
      • Warren J.
      • Rose K.L.
      • Carlucci F.
      • Wang Y.
      • Walport M.J.
      • et al.
      Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice.
      Although spontaneous MPGN with capillary wall deposits was still observed, glomerular cellularity/crescents were reduced with improved renal function and reduced mortality. Cfh−/− mice with accompanying C5 deficiency also were less susceptible to renal injury induced by sheep nephrotoxic serum, whereas Cfh−/− mice with or without accompanying C6 deficiency showed an influx of neutrophils into the glomerulus. This suggests that the production of C5a rather than membrane attack complex (MAC) formation mediated renal damage. Cfh−/− mice injected with anti-C5 antibodies before administration of nephrotoxic serum also were protected, suggesting that anti-C5 therapy may be beneficial in human beings with C3 glomerulopathy owing to Cfh deficiency (eg, during disease flares). In mice with homozygous deficiency of Cfi, an inability to metabolize C3b results in uncontrolled AP activation and low circulating C3 levels. In Cfi−/− mice only C3b is evident in plasma, consistent with the C3 profile in human beings with total Cfi deficiency.
      • Vyse T.J.
      • Spath P.J.
      • Davies K.A.
      • Morley B.J.
      • Philippe P.
      • Athanassiou P.
      • et al.
      Hereditary complement factor I deficiency.
      Cfi−/− mice show mesangial C3 accumulation and nodular mesangial expansion, but without GBM C3 staining or features of MPGN. Unexpectedly, in mice with combined homozygous deficiency of Cfh and Cfi, both the plasma C3 profile and glomerular C3 pattern are identical to those seen in Cfi deficiency alone.
      • Rose K.L.
      • Paixão-Cavalcante D.
      • Fish J.
      • Manderson A.P.
      • Malik T.H.
      • Bygrave A.E.
      • et al.
      Factor I is required for the development of membranoproliferative glomerulonephritis in factor H-deficient mice.
      Injection into Cfh−/−.Cfi−/− mice of a source of murine Cfi resulted in cleavage of C3b, generating fragments including iC3b. This was accompanied by loss of mesangial C3 staining, and the appearance of GBM C3 staining. It therefore appears that cleavage of C3b was critical for GBM C3 staining to occur, and that measures to prevent conversion of C3b to iC3b might be useful therapeutically in patients in whom GBM C3 accumulation is shown.
      Recently, an additional aspect of renal pathogenesis was elucidated through the generation of mice with Cfh and properdin deficiency.
      • Ruseva M.M.
      • Vernon K.A.
      • Lesher A.M.
      • Schwaeble W.J.
      • Ali Y.M.
      • Botto M.
      • et al.
      Loss of properdin exacerbates c3 glomerulopathy resulting from factor h deficiency.
      • Lesher A.M.
      • Zhou L.
      • Kimura Y.
      • Sato S.
      • Gullipalli D.
      • Herbert A.P.
      • et al.
      Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis.
      Because properdin prolongs the cleaving activity of the AP C3 convertase, it was hypothesized that genetic deficiency of properdin (as a positive regulator of the AP) would ameliorate the renal phenotype of Cfh deficiency. Unexpectedly, Cfh−/−.P−/− mice showed more severe MPGN and more intense GBM C3 staining than Cfh−/− mice.
      • Ruseva M.M.
      • Vernon K.A.
      • Lesher A.M.
      • Schwaeble W.J.
      • Ali Y.M.
      • Botto M.
      • et al.
      Loss of properdin exacerbates c3 glomerulopathy resulting from factor h deficiency.
      Plasma C3 levels did not differ between Cfh−/−.P−/− and Cfh−/− mice, although only Cfh−/−.P−/− mice showed (fractional amounts of) intact C3. Plasma C5 was absent in Cfh−/− mice (consistent with previous data
      • Goicoechea de Jorge E.
      • Macor O.
      • Paixão-Cavalcante D.
      • Rose K.L.
      • Tedesco F.
      • Cook H.T.
      • et al.
      The development of atypical hemolytic uremic syndrome depends on complement C5.
      ), but was detected at low levels in Cfh−/−.P−/− mice. One explanation for these observations is that higher levels of intact C3 in Cfh−/−.P−/− mice may increase the availability of iC3b in the circulation for accumulation along the GBM, whereas the increased availability of C5 also may contribute to the more severe glomerular inflammation seen in these mice. Although the predominant C3 depletion seen in Cfh−/−.P−/− mice closely resembles the C3 profile in human subjects with properdin-independent C3NeFs, the pattern of C3 and C5 depletion in Cfh−/− mice is analogous to properdin-dependent C3NeFs.

      Treatment

      No treatment has been proven to be beneficial in C3 glomerulopathy.
      Antihypertensive/antiproteinuric therapy, particularly via renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, generally is recommended in GN.
      Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group
      KDIGO Clinical Practice Guideline for Glomerulonephritis. General principles in the management of glomerular disease.
      Evidence in support of RAAS blockade in C3 glomerulopathy specifically is limited to retrospective cohort studies (which are subject to treatment bias). In the French C3 glomerulopathy cohort, RAAS blockade, but not use of immunosuppressants, was associated with a significant increase in renal survival,
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      whereas in the US DDD cohort a nonsignificant reduction in progression to ESKD was found with combined RAAS blockade and steroids.
      • Nasr S.H.
      • Valeri A.M.
      • Appel G.B.
      • Sherwinter J.
      • Stokes M.B.
      • Said S.M.
      • et al.
      Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.
      After early reports of children with DDD in whom alternate-day steroids were associated with histologic regression,
      • McEnery P.T.
      • McAdams A.J.
      Regression of membranoproliferative glomerulonephritis type II (dense deposit disease): observations in six children.
      a 1992 randomized controlled trial showed clinical benefit in 70 children with MPGN, of whom 14 had DDD (without a subgroup analysis).
      • Tarshish P.
      • Bernstein J.
      • Tobin J.N.
      • Edelmann Jr., C.M.
      Treatment of mesangiocapillary glomerulonephritis with alternate-day prednisone--a report of the International Study of Kidney Disease in Children.
      In the absence of subsequent randomized controlled trials, reports purportedly showing response to steroids in DDD are complicated by the highly variable natural history, which includes rare occurrences of sustained clinical remission even without treatment.
      • Marks S.D.
      • Rees L.
      Spontaneous clinical improvement in dense deposit disease.
      • Ikeda M.
      • Honda M.
      • Hasegawa O.
      Another example of spontaneous improvement in a case of dense deposit disease.
      Thus, in one pediatric series of likely C3 glomerulopathy, treatment with steroids, initiated on the basis of biopsy evidence of acute glomerular inflammation including crescents, led to clinical improvement in a number of cases.
      • West C.D.
      • McAdams A.J.
      • Witte D.P.
      Acute non-proliferative glomerulitis: a cause of renal failure unique to children.
      However, an identical improvement was seen in an untreated patient. Use of steroids and immunosuppressants may appear most justified in patients with C3 glomerulopathy who develop rapidly progressive GN (because this would prompt their use for other causes of GN). However, post-transplant recurrence of C3 glomerulopathy (including with crescents on biopsy, discussed later) and aHUS
      • Barbour T.
      • Johnson S.
      • Cohney S.
      • Hughes P.
      Thrombotic microangiopathy and associated renal disorders.
      suggests that immunosuppression (as used in the transplant period) may be ineffective for AP-mediated renal disease. The iatrogenic risk of infection, potentially triggering complement activation and exacerbation of nephritis, also must be weighed. Treatment with the anti-CD20 monoclonal antibody rituximab has been reported with success in a single case of DDD related to anti-Cfb/C3b autoantibodies.
      • Chen Q.
      • Müller D.
      • Rudolph B.
      • Hartmann A.
      • Kuwertz-Bröking E.
      • Wu K.
      • et al.
      Combined C3b and factor B autoantibodies and MPGN type II.
      Immunosuppressive treatment for underlying hematologic malignancies including MGUS, in patients with associated C3 glomerulopathy, leading to improvement in renal parameters in some reports
      • Zand L.
      • Kattah A.
      • Fervenza F.C.
      • Smith R.J.
      • Nasr S.H.
      • Zhang Y.
      • et al.
      C3 glomerulonephritis associated with monoclonal gammopathy: a case series.
      but not others,
      • Bridoux F.
      • Desport E.
      • Frémeaux-Bacchi V.
      • Chong C.F.
      • Gombert J.M.
      • Lacombe C.
      • et al.
      Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association?.
      is not discussed here.
      Restoration of normal AP regulation is a major goal of current research into treatment of C3 glomerulopathy. The animal models suggest that purified or recombinant Cfh replacement might be beneficial in Cfh-deficient patients. Although this therapy is not currently available, long-term plasma infusion was effective and well tolerated in the sisters with familial C3GN related to circulating mutant Cfh.
      • Licht C.
      • Heinen S.
      • Józsi M.
      • Loschmann I.
      • Saunders R.E.
      • Perkins S.J.
      • et al.
      Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II).
      Elsewhere plasma infusion/exchange has been reported with only mixed success, including in the setting of recurrent post-transplant DDD.
      • Kurtz K.A.
      • Schlueter A.J.
      Management of membranoproliferative glomerulonephritis type II with plasmapheresis.
      A therapeutic role for anti-C5/C5a therapy in C3 glomerulopathy flares is suggested by experimental data in animal models and by the observation in DDD patients with rapidly progressive GN that the glomerular deposits contain C5.
      • West C.D.
      • Witte D.P.
      • McAdams A.J.
      Composition of nephritic factor-generated glomerular deposits in membranoproliferative glomerulonephritis type 2.
      The C5-inhibitor eculizumab has been reported with success in several cases of DDD
      • Daina E.
      • Noris M.
      • Remuzzi G.
      Eculizumab in a patient with dense-deposit disease.
      • Vivarelli M.
      • Pasini A.
      • Emma F.
      Eculizumab for the treatment of dense-deposit disease.
      (including a patient with post-transplant recurrence associated with renal failure
      • McCaughan J.A.
      • O'Rourke D.M.
      • Courtney A.E.
      Recurrent dense deposit disease after renal transplantation: an emerging role for complementary therapies.
      ) and one of MPGN type 1.
      • Radhakrishnan S.
      • Lunn A.
      • Kirschfink M.
      • Thorner P.
      • Hebert D.
      • Langlois V.
      • et al.
      Eculizumab and refractory membranoproliferative glomerulonephritis.
      However, it also has been reported with failure in another DDD patient,
      • Daina E.
      • Noris M.
      • Remuzzi G.
      Eculizumab in a patient with dense-deposit disease.
      and with mixed results in a recent prospective, uncontrolled trial in 6 adults with native or recurrent post-transplant DDD or C3GN.
      • Bomback A.S.
      • Smith R.J.
      • Barile G.R.
      • Zhang Y.
      • Heher E.C.
      • Herlitz L.
      • et al.
      Eculizumab for dense deposit disease and C3 glomerulonephritis.
      At the conclusion of a 1-year course of eculizumab, a clinical improvement was observed in three of the trial patients (two showing reduced inflammation on biopsy
      • Herlitz L.C.
      • Bomback A.S.
      • Markowitz G.S.
      • Stokes M.B.
      • Smith R.N.
      • Colvin R.B.
      • et al.
      Pathology after eculizumab in dense deposit disease and C3 GN.
      ). In the future, agents that either inhibit the C3 convertase of the AP or remove C3 (and/or C3 fragments) from the circulation may undergo evaluation (bearing in mind the key protective functions these molecules also perform in innate immunity).

      Transplantation

      Histologic recurrence of DDD after renal transplantation was first reported by Galle et al
      • Galle P.
      • Hinglais N.
      • Crosnier J.
      Recurrence of an original glomerular lesion in three renal allografts.
      and is common.
      • Andresdottir M.B.
      • Assmann K.J.
      • Hoitsma A.J.
      • Koene R.A.
      • Wetzels J.F.
      Renal transplantation in patients with dense deposit disease: morphological characteristics of recurrent disease and clinical outcome.
      Histologic recurrence of C3GN probably also was described in older studies,
      • Hamburger J.
      • Crosnier J.
      • Noël L.H.
      Recurrent glomerulonephritis after renal transplantation.
      with recent reports
      • Servais A.
      • Noël L.H.
      • Roumenina L.T.
      • Le Quintrec M.
      • Ngo S.
      • Dragon-Durey M.A.
      • et al.
      Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
      • Sethi S.
      • Fervenza F.C.
      • Zhang Y.
      • Zand L.
      • Vrana J.A.
      • Nasr S.H.
      • et al.
      C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.
      including cases of CFHR5 nephropathy
      • Vernon K.A.
      • Gale D.P.
      • Goicoechea de Jorge E.
      • McLean A.G.
      • Galliford J.
      • Pierides A.
      • et al.
      Recurrence of complement factor H-related protein 5 nephropathy in a renal transplant.
      and the CFHR3/1 hybrid gene (in which the related donor also later developed C3 glomerulopathy).
      • Neary J.
      • Dorman A.
      • Campbell E.
      • Keogan M.
      • Conlon P.
      Familial membranoproliferative glomerulonephritis type III.
      A US retrospective cohort of almost 8,000 pediatric transplant recipients, including 75 children with DDD, assessed the impact of histologic recurrence of DDD on graft survival.
      • Braun M.C.
      • Stablein D.M.
      • Hamiwka L.A.
      • Bell L.
      • Bartosh S.M.
      • Strife C.F.
      Recurrence of membranoproliferative glomerulonephritis type II in renal allografts: the North American Pediatric Renal Transplant Cooperative Study experience.
      At 5 years, 50% of pediatric DDD recipients had viable grafts (comparable with the 45% rate identified in an accompanying literature review of 78 pediatric and adult DDD recipients). This was significantly lower than the pediatric graft survival rate of 74% in all-cause ESKD and 72% in non-DDD forms of GN. Of 29 graft failures in DDD recipients during the study period, 11 were attributed to recurrent disease (9 after deceased donor transplantation). However, the contribution of recurrent disease to the overall increase in pediatric graft failure rates in DDD recipients was not assessed, except in a subgroup of 29 of the DDD recipients. Here, 4 graft losses resulting from biopsy-proven recurrent disease represented a nonsignificant reduction in median graft survival. Of note, crescents were seen on graft biopsy only in those with evidence of DDD recurrence, and were significantly associated with reduced graft survival. Biopsy-proven recurrence was always accompanied by heavy proteinuria, but no clinical or laboratory variables predicted either DDD recurrence or graft loss. The investigators concluded that there was no correlation between the isolated recurrence of dense deposits and reduced graft survival.
      • Braun M.C.
      • Stablein D.M.
      • Hamiwka L.A.
      • Bell L.
      • Bartosh S.M.
      • Strife C.F.
      Recurrence of membranoproliferative glomerulonephritis type II in renal allografts: the North American Pediatric Renal Transplant Cooperative Study experience.
      More recent studies include an Irish cohort of 33 patients with primary idiopathic MPGN in whom graft failure rates were reported only for those with biopsy-proven recurrence.
      • Little M.A.
      • Dupont P.
      • Campbell E.
      • Dorman A.
      • Walshe J.J.
      Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk.
      This included 11 of a total of 18 transplants performed in recipients with (nonfamilial) DDD. The investigators concluded that 14 grafts lost to recurrent MPGN at a median of 7.5 years was likely to represent a reduction in graft half-life.
      • Little M.A.
      • Dupont P.
      • Campbell E.
      • Dorman A.
      • Walshe J.J.
      Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk.
      In the US questionnaire-based DDD study comprising 22 mostly pediatric transplant recipients, 10 grafts were lost within the first 5 years (7 were attributed to recurrent disease).
      • Lu D.F.
      • Moon M.
      • Lanning L.D.
      • McCarthy A.M.
      • Smith R.J.
      Clinical features and outcomes of 98 children and adults with dense deposit disease.
      In one C3GN cohort, post-transplant recurrence in two individuals was heralded by increased creatinine levels, subnephrotic proteinuria, and low serum C3 levels.
      • Sethi S.
      • Fervenza F.C.
      • Zhang Y.
      • Zand L.
      • Vrana J.A.
      • Nasr S.H.
      • et al.
      C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.
      In CFHR nephropathy, 10 patients (mostly males) have been reported with successful transplantation (including a recipient whose female related donor was an asymptomatic carrier of the mutation), despite histologic recurrence in all three patients who underwent a biopsy.
      • Athanasiou Y.
      • Voskarides K.
      • Gale D.P.
      • Damianou L.
      • Patsias C.
      • Zavros M.
      • et al.
      Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.
      • Vernon K.A.
      • Gale D.P.
      • Goicoechea de Jorge E.
      • McLean A.G.
      • Galliford J.
      • Pierides A.
      • et al.
      Recurrence of complement factor H-related protein 5 nephropathy in a renal transplant.

      Conclusions

      DDD is distinguished histologically from other forms of C3 glomerulopathy by the presence of osmiophilic, intramembranous, ribbon-like deposits. Certain clinical features, including a young age at diagnosis and (in rare cases) an association with ocular drusen, are more typical of DDD than other forms of C3 glomerulopathy. A diagnosis of DDD does not appear to confer a worse renal prognosis compared with other forms of C3 glomerulopathy. Evidence for the role of AP dysregulation in C3 glomerulopathy is drawn from linkage studies in a small number of pedigrees, cohort studies showing an association with C3NeFs and complement regulatory gene variants, and animal models. Recently, linkage was shown for copy number variation across different CFHR genes in familial C3 glomerulopathy, and a new pathophysiologic concept of Cfh deregulation has been proposed. Because progression to ESKD and post-transplant recurrence is common in all forms of C3 glomerulopathy, therapies that target underlying disease mechanisms are urgently required.
      • Neary J.
      • Dorman A.
      • Campbell E.
      • Keogan M.
      • Conlon P.
      Familial membranoproliferative glomerulonephritis type III.
      • Neary J.J.
      • Conlon P.J.
      • Croke D.
      • Dorman A.
      • Keogan M.
      • Zhang F.Y.
      • et al.
      Linkage of a gene causing familial membranoproliferative glomerulonephritis type III to chromosome 1.
      • Malik T.H.
      • Lavin P.J.
      • Goicoechea de Jorge E.
      • Vernon K.A.
      • Rose K.L.
      • Patel M.P.
      • et al.
      A hybrid CFHR3-1 gene causes familial C3 glomerulopathy.
      • Berry P.L.
      • McEnery P.T.
      • McAdams A.J.
      • West C.D.
      Membranoproliferative glomerulonephritis in two sibships.
      • Marder H.K.
      • Coleman T.H.
      • Forristal J.
      • Beischel L.
      • West C.D.
      An inherited defect in the C3 convertase, C3b, Bb, associated with glomerulonephritis.
      • Linshaw M.A.
      • Stapleton F.B.
      • Cuppage F.E.
      • Forristal J.
      • West C.D.
      • Schreiber R.D.
      • et al.
      Hypocomplementemic glomerulonephritis in an infant and mother. Evidence for an abnormal form of C3.
      • Lopez-Larrea C.
      • Dieguez M.
      • Enguix A.
      • Dominguez O.
      • Marín B.
      • Gomez E.
      A familial deficiency of complement factor H.
      • Herrin J.T.
      • Bartsocas C.S.
      Familial membranoproliferative glomerulonephritis type 2 (MPGN-2).
      • Power D.A.
      • Ng Y.C.
      • Simpson J.G.
      Familial incidence of C3 nephritic factor, partial lipodystrophy and membranoproliferative glomerulonephritis.
      • López-Trascasa M.
      • Martín-Villa J.M.
      • Vicario J.L.
      • Marín M.A.
      • Martínez-Ara J.
      • García-Messeguer M.C.
      • et al.
      Familial incidence of C3 nephritic factor.
      • Motoyama O.
      • Sakai K.
      • Ohashi Y.
      • Mizuiri S.
      • Hatori T.
      • Iitaka K.
      • et al.
      Membranoproliferative glomerulonephritis in a girl and her mother.

      References

        • Berger J.
        • Galle P.
        Altération singulière des membranes basales du rein.
        J Urol Néphrol (Paris). 1962; 68: 116-122
        • Berger J.
        • Galle P.
        Dépôts denses au sein des membranes basales du rein: étude en microscopies optique et électronique.
        Presse Med. 1963; 71: 2351-2354
        • Walker P.D.
        • Ferrario F.
        • Joh K.
        • Bonsib S.M.
        Dense deposit disease is not a membranoproliferative glomerulonephritis.
        Mod Pathol. 2007; 20: 605-616
        • Nasr S.H.
        • Valeri A.M.
        • Appel G.B.
        • Sherwinter J.
        • Stokes M.B.
        • Said S.M.
        • et al.
        Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients.
        Clin J Am Soc Nephrol. 2009; 4: 22-32
        • Wang J.
        • Tang Z.
        • Luo C.
        • Hu Y.
        • Zeng C.
        • Chen H.
        • et al.
        Clinical and pathological features of dense deposit disease in Chinese patients.
        Clin Nephrol. 2012; 78: 207-215
        • Braun M.C.
        • Stablein D.M.
        • Hamiwka L.A.
        • Bell L.
        • Bartosh S.M.
        • Strife C.F.
        Recurrence of membranoproliferative glomerulonephritis type II in renal allografts: the North American Pediatric Renal Transplant Cooperative Study experience.
        J Am Soc Nephrol. 2005; 16: 2225-2233
        • Habib R.
        • Kleinknecht C.
        • Gubler M.C.
        • Maïz H.B.
        Idiopathic membranoproliferative glomerulonephritis. Morphology and natural history.
        Perspect Nephrol Hypertens. 1973; 1: 491-514
        • Berger J.
        • Yaneva H.
        • Antoine B.
        Étude immunohistochimique des lésions glomérulaires.
        J Urol Néphrol (Paris). 1969; 76: 269-281
        • Bariéty J.
        • Druet P.
        • Loirat P.
        • Lagrue G.
        Les glomérulonéphrites pariétoprolifératives glomerulonephritis (G.N.P.P). Étude histopathologique en microcopie optique, électronique et en immunohistochimie de 49 cas. Corrélations anatomocliniques.
        Pathol Biol (Paris). 1971; 19: 259-283
        • Servais A.
        • Frémeaux-Bacchi V.
        • Lequintrec M.
        • Salomon R.
        • Blouin J.
        • Knebelmann B.
        • 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: 193-199
        • Fakhouri F.
        • Frémeaux-Bacchi V.
        • Noël L.H.
        • Cook H.T.
        • Pickering M.C.
        C3 glomerulopathy: a new classification.
        Nat Rev Nephrol. 2010; 6: 494-499
        • Vernon K.A.
        • Goicoechea de Jorge E.
        • Hall A.E.
        • Frémeaux-Bacchi V.
        • Aitman T.J.
        • Cook H.T.
        • et al.
        Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency.
        Am J Kidney Dis. 2012; 60: 121-125
        • Sandhu G.
        • Bansal A.
        • Ranade A.
        • Jones J.
        • Cortell S.
        • Markowitz G.S.
        C3 glomerulopathy masquerading as acute postinfectious glomerulonephritis.
        Am J Kidney Dis. 2012; 60: 1039-1043
        • Sethi S.
        • Fervenza F.C.
        • Zhang Y.
        • Zand L.
        • Meyer N.C.
        • Borsa N.
        • et al.
        Atypical postinfectious glomerulonephritis is associated with abnormalities in the alternative pathway of complement.
        Kidney Int. 2013; 83: 293-299
        • Meleg-Smith S.
        The many faces of C3 glomerulopathy.
        Kidney Int. 2012; 82: 611
        • Pickering M.C.
        • Cook H.T.
        Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals.
        Clin Exp Immunol. 2008; 151: 210-230
        • Sethi S.
        • Fervenza F.C.
        • Zhang Y.
        • Nasr S.H.
        • Leung N.
        • Vrana J.
        • et al.
        Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement.
        Clin J Am Soc Nephrol. 2011; 6: 1009-1017
        • Bridoux F.
        • Desport E.
        • Frémeaux-Bacchi V.
        • Chong C.F.
        • Gombert J.M.
        • Lacombe C.
        • et al.
        Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association?.
        Clin J Am Soc Nephrol. 2011; 6: 2165-2174
        • Hawfield A.
        • Iskandar S.S.
        • Smith R.J.
        Alternative pathway dysfunction in kidney disease: a case report and review of dense deposit disease and C3 glomerulopathy.
        Am J Kidney Dis. 2013; 61: 828-831
      1. Strife CF, West CD, Witte DP. Crescentic glomerulonephritis in childhood: acute nonproliferative glomerulitis versus dense deposit disease. Am J Kidney Dis. 2003;41:897; author reply 898.

        • Servais A.
        • Noël L.H.
        • Roumenina L.T.
        • Le Quintrec M.
        • Ngo S.
        • Dragon-Durey M.A.
        • et al.
        Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
        Kidney Int. 2012; 82: 454-464
        • Strife C.F.
        • McEnery P.T.
        • McAdams A.J.
        • West C.D.
        Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane.
        Clin Nephrol. 1977; 7: 65-72
        • West C.D.
        • Witte D.P.
        • McAdams A.J.
        Composition of nephritic factor-generated glomerular deposits in membranoproliferative glomerulonephritis type 2.
        Am J Kidney Dis. 2001; 37: 1120-1130
        • West C.D.
        • McAdams A.J.
        Paramesangial glomerular deposits in membranoproliferative glomerulonephritis type II correlate with hypocomplementemia.
        Am J Kidney Dis. 1995; 25: 853-861
        • Sethi S.
        • Gamez J.D.
        • Vrana J.A.
        • Theis J.D.
        • Bergen III, H.R.
        • Zipfel P.F.
        • et al.
        Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway.
        Kidney Int. 2009; 75: 952-960
        • Smith R.J.
        • Harris C.L.
        • Pickering M.C.
        Dense deposit disease.
        Mol Immunol. 2011; 48: 1604-1610
        • Galle P.
        • Mahieu P.
        Electron dense alteration of kidney basement membranes. A renal lesion specific of a systemic disease.
        Am J Med. 1975; 58: 749-764
        • Donadio Jr, J.V.
        • Slack T.K.
        • Holley K.E.
        • Ilstrup D.M.
        Idiopathic membranoproliferative (mesangiocapillary) glomerulonephritis: a clinicopathologic study.
        Mayo Clin Proc. 1979; 54: 141-150
        • Cameron J.S.
        • Turner D.R.
        • Heaton J.
        • Williams D.G.
        • Ogg C.S.
        • Chantler C.
        • et al.
        Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis.
        Am J Med. 1983; 74: 175-192
        • Little M.A.
        • Dupont P.
        • Campbell E.
        • Dorman A.
        • Walshe J.J.
        Severity of primary MPGN, rather than MPGN type, determines renal survival and post-transplantation recurrence risk.
        Kidney Int. 2006; 69: 504-511
        • Swainson C.P.
        • Robson J.S.
        • Thomson D.
        • MacDonald M.K.
        Mesangiocapillary glomerulonephritis: a long-term study of 40 cases.
        J Pathol. 1983; 141: 449-468
        • Bohle A.
        • Gärtner H.V.
        • Fischbach H.
        • Bock K.D.
        • Edel H.H.
        • Frotscher U.
        • et al.
        The morphological and clinical features of membranoproliferative glomerulonephritis in adults.
        Virchows Arch A Pathol Anat Histol. 1974; 363: 213-224
        • Klein M.
        • Poucell S.
        • Arbus G.S.
        • McGraw M.
        • Rance C.P.
        • Yoon S.J.
        • et al.
        Characteristics of a benign subtype of dense deposit disease: comparison with the progressive form of this disease.
        Clin Nephrol. 1983; 20: 163-171
        • Bennett W.M.
        • Fassett R.G.
        • Walker R.G.
        • Fairley K.F.
        • d'Apice A.J.
        • Kincaid-Smith P.
        Mesangiocapillary glomerulonephritis type II (dense-deposit disease): clinical features of progressive disease.
        Am J Kidney Dis. 1989; 13: 469-476
        • Antoine B.
        • Faye C.
        The clinical course associated with dense deposits in the kidney basement membranes.
        Kidney Int. 1972; 1: 420-427
        • Park S.J.
        • Kim Y.J.
        • Ha T.S.
        • Lim B.J.
        • Jeong H.J.
        • Park Y.H.
        • et al.
        Dense deposit disease in Korean children: a multicenter clinicopathologic study.
        J Korean Med Sci. 2012; 27: 1215-1221
        • Lu D.F.
        • Moon M.
        • Lanning L.D.
        • McCarthy A.M.
        • Smith R.J.
        Clinical features and outcomes of 98 children and adults with dense deposit disease.
        Pediatr Nephrol. 2012; 27: 773-781
        • Habib R.
        • Gubler M.C.
        • Loirat C.
        • Maïz H.B.
        • Levy M.
        Dense deposit disease: a variant of membranoproliferative glomerulonephritis.
        Kidney Int. 1975; 7: 204-215
        • Vargas R.
        • Thomson K.J.
        • Wilson D.
        • Cameron J.S.
        • Turner D.R.
        • Gill D.
        • et al.
        Mesangiocapillary glomerulonephritis with dense "deposits" in the basement membranes of the kidney.
        Clin Nephrol. 1976; 5: 73-82
        • Davis A.E.
        • Schneeberger E.E.
        • Grupe W.E.
        • McCluskey R.T.
        Membranoproliferative glomerulonephritis (MPGN type I) and dense deposit disease (DDD) in children.
        Clin Nephrol. 1978; 9: 184-193
        • Kashtan C.E.
        • Burke B.
        • Burch G.
        • Gustav Fisker S.
        • Kim Y.
        Dense intramembranous deposit disease: a clinical comparison of histological subtypes.
        Clin Nephrol. 1990; 33: 1-6
        • Sethi S.
        • Fervenza F.C.
        • Zhang Y.
        • Zand L.
        • Vrana J.A.
        • Nasr S.H.
        • et al.
        C3 glomerulonephritis: clinicopathological findings, complement abnormalities, glomerular proteomic profile, treatment, and follow-up.
        Kidney Int. 2012; 82: 465-473
        • Berger J.
        • Hinglais N.
        Les dépôts intercapillaires d'IgA-IgG.
        J Urol Nephrol (Paris). 1968; 74: 694-695
        • Levy M.
        • Halbwachs-Mecarelli L.
        • Gubler M.C.
        • Kohout G.
        • Bensenouci A.
        • Niaudet P.
        • et al.
        H deficiency in two brothers with atypical dense intramembranous deposit disease.
        Kidney Int. 1986; 30: 949-956
        • Lamb V.
        • Tisher C.C.
        • McCoy R.C.
        • Robinson R.R.
        Membranoproliferative glomerulonephritis with dense intramembranous alterations. A clinicopathologic study.
        Lab Invest. 1977; 36: 607-617
        • Jenis E.H.
        • Sandler P.
        • Hill G.S.
        • Knieser M.R.
        • Jensen G.E.
        • Roskes S.D.
        Glomerulonephritis with basement membrane dense deposits.
        Arch Pathol. 1974; 97: 84-91
        • Duvall-Young J.
        • MacDonald M.K.
        • McKechnie N.M.
        Fundus changes in (type II) mesangiocapillary glomerulonephritis simulating drusen: a histopathological report.
        Br J Ophthalmol. 1989; 73: 297-302
        • Mullins R.F.
        • Aptsiauri N.
        • Hageman G.S.
        Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis.
        Eye (Lond). 2001; 15: 390-395
        • Appel G.B.
        • Cook H.T.
        • Hageman G.
        • Jennette J.C.
        • Kashgarian M.
        • Kirschfink M.
        • et al.
        Membranoproliferative glomerulonephritis type II (dense deposit disease): an update.
        J Am Soc Nephrol. 2005; 16: 1392-1403
        • Bomback A.S.
        • Smith R.J.
        • Barile G.R.
        • Zhang Y.
        • Heher E.C.
        • Herlitz L.
        • et al.
        Eculizumab for dense deposit disease and C3 glomerulonephritis.
        Clin J Am Soc Nephrol. 2012; 7: 748-756
        • Gellis S.
        • Green S.
        • Walker D.
        Chronic renal disease in children.
        Am J Dis Child. 1958; 96: 605-611
        • Eisinger A.J.
        • Shortland J.R.
        • Moorhead P.J.
        Renal disease in partial lipodystrophy.
        QJM. 1972; 41: 343-354
        • Williams D.G.
        • Scopes J.W.
        • Peters D.K.
        Hypocomplementaemic membranoproliferative glomerulonephritis and nephrotic syndrome associated with partial lipodystrophy of the face and trunk.
        Proc R Soc Med. 1972; 65: 591
        • Nasr S.H.
        • Satoskar A.
        • Markowitz G.S.
        • Valeri A.M.
        • Appel G.B.
        • Stokes M.B.
        • et al.
        Proliferative glomerulonephritis with monoclonal IgG deposits.
        J Am Soc Nephrol. 2009; 20: 2055-2064
        • Sissons J.G.
        • West R.J.
        • Fallows J.
        • Williams D.G.
        • Boucher B.J.
        • Amos N.
        • et al.
        The complement abnormalities of lipodystrophy.
        N Engl J Med. 1976; 294: 461-465
        • Hamza M.
        • Levy M.
        • Broyer M.
        • Habib R.
        Deux cas de glomérulo-néphrite membrano-proliférative avec lipodystrophie partielle de type facio-tronculaire.
        J Urol Néphrol (Paris). 1970; 76: 1032-1042
        • Misra A.
        • Peethambaram A.
        • Garg A.
        Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: report of 35 cases and review of the literature.
        Medicine (Baltimore). 2004; 83: 18-34
        • Sepandj F.
        • Trillo A.
        Dense deposit disease in association with monoclonal gammopathy of unknown significance.
        Nephrol Dial Transplant. 1996; 11: 2309-2312
        • Sethi S.
        • Sukov W.R.
        • Zhang Y.
        • Fervenza F.C.
        • Lager D.J.
        • Miller D.V.
        • et al.
        Dense deposit disease associated with monoclonal gammopathy of undetermined significance.
        Am J Kidney Dis. 2010; 56: 977-982
        • Zand L.
        • Kattah A.
        • Fervenza F.C.
        • Smith R.J.
        • Nasr S.H.
        • Zhang Y.
        • et al.
        C3 glomerulonephritis associated with monoclonal gammopathy: a case series.
        Am J Kidney Dis. 2013; 62: 506-514
        • Schwertz R.
        • de Jong R.
        • Gretz N.
        • Kirschfink M.
        • Anders D.
        • Schärer K.
        Outcome of idiopathic membranoproliferative glomerulonephritis in children.
        Arbeitsgemeinschaft Padiatrische Nephrologie. Acta Paediatr. 1996; 85: 308-312
        • Smith R.J.
        • Alexander J.
        • Barlow P.N.
        • Botto M.
        • Cassavant T.L.
        • Cook H.T.
        • et al.
        New approaches to the treatment of dense deposit disease.
        J Am Soc Nephrol. 2007; 18: 2447-2456
        • Cansick J.C.
        • Lennon R.
        • Cummins C.L.
        • Howie A.J.
        • McGraw M.E.
        • Saleem M.A.
        • et al.
        Prognosis, treatment and outcome of childhood mesangiocapillary (membranoproliferative) glomerulonephritis.
        Nephrol Dial Transplant. 2004; 19: 2769-2777
        • di Belgiojoso B.
        • Tarantino A.
        • Colasanti G.
        • Bazzi C.
        • Guerra L.
        • Durante A.
        The prognostic value of some clinical and histological parameters in membranoproliferative glomerulonephritis (MPGN): report of 112 cases.
        Nephron. 1977; 19: 250-258
        • Somers M.
        • Kertesz S.
        • Rosen S.
        • Herrin J.
        • Colvin R.
        • Palacios de Carreta N.
        • et al.
        Non-nephrotic children with membranoproliferative glomerulonephritis: are steroids indicated?.
        Pediatr Nephrol. 1995; 9: 140-144
        • Miller M.N.
        • Baumal R.
        • Poucell S.
        • Steele B.T.
        Incidence and prognostic importance of glomerular crescents in renal diseases of childhood.
        Am J Nephrol. 1984; 4: 244-247
        • Spitzer R.E.
        • Vallota E.H.
        • Forristal J.
        • Sudora E.
        • Stitzel A.
        • Davis N.C.
        • et al.
        Serum C'3 lytic system in patients with glomerulonephritis.
        Science. 1969; 164: 436-437
        • Daha M.R.
        • Fearon D.T.
        • Austen K.F.
        C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase.
        J Immunol. 1976; 116: 1-7
        • Mollnes T.E.
        • Ng Y.C.
        • Peters D.K.
        • Lea T.
        • Tschopp J.
        • Harboe M.
        Effect of nephritic factor on C3 and on the terminal pathway of complement in vivo and in vitro.
        Clin Exp Immunol. 1986; 65: 73-79
        • Clardy C.W.
        • Forristal J.
        • Strife C.F.
        • West C.D.
        A properdin dependent nephritic factor slowly activating C3, C5, and C9 in membranoproliferative glomerulonephritis, types I and III.
        Clin Immunol Immunopathol. 1989; 50: 333-347
        • Tanuma Y.
        • Ohi H.
        • Hatano M.
        Two types of C3 nephritic factor: properdin-dependent C3NeF and properdin-independent C3NeF.
        Clin Immunol Immunopathol. 1990; 56: 226-238
        • Schwertz R.
        • Rother U.
        • Anders D.
        • Gretz N.
        • Schärer K.
        • Kirschfink M.
        Complement analysis in children with idiopathic membranoproliferative glomerulonephritis: a long-term follow-up.
        Pediatr Allergy Immunol. 2001; 12: 166-172
        • Zhang Y.
        • Meyer N.C.
        • Wang K.
        • Nishimura C.
        • Frees K.
        • Jones M.
        • et al.
        Causes of alternative pathway dysregulation in dense deposit disease.
        Clin J Am Soc Nephrol. 2012; 7: 265-274
        • Gale D.P.
        • Goicoechea de Jorge E.
        • Cook H.T.
        • Martínez-Barricarte R.
        • Hadjisavvas A.
        • McLean A.G.
        • et al.
        Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis.
        Lancet. 2010; 376: 794-801
        • Strobel S.
        • Zimmering M.
        • Papp K.
        • Prechl J.
        • Józsi M.
        Anti-factor B autoantibody in dense deposit disease.
        Mol Immunol. 2010; 47: 1476-1483
        • Chen Q.
        • Müller D.
        • Rudolph B.
        • Hartmann A.
        • Kuwertz-Bröking E.
        • Wu K.
        • et al.
        Combined C3b and factor B autoantibodies and MPGN type II.
        N Engl J Med. 2011; 365: 2340-2342
        • Meri S.
        • Koistinen V.
        • Miettinen A.
        • Törnroth T.
        • Seppälä I.J.
        Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis.
        J Exp Med. 1992; 175: 939-950
        • Jokiranta T.S.
        • Solomon A.
        • Pangburn M.K.
        • Zipfel P.F.
        • Meri S.
        Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H.
        J Immunol. 1999; 163: 4590-4596
        • Goodship T.H.
        • Pappworth I.Y.
        • Toth T.
        • Denton M.
        • Houlberg K.
        • McCormick F.
        • et al.
        Factor H autoantibodies in membranoproliferative glomerulonephritis.
        Mol Immunol. 2012; 52: 200-206
        • Dragon-Durey M.A.
        • Frémeaux-Bacchi V.
        • Loirat C.
        • Blouin J.
        • Niaudet P.
        • Deschenes G.
        • et al.
        Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases.
        J Am Soc Nephrol. 2004; 15: 787-795
        • Rusai K.
        • Zaller V.
        • Szilagyi A.
        • Kain R.
        • Prohaszka Z.
        • Cook H.T.
        • et al.
        A rare case: childhood-onset C3 glomerulonephritis due to homozygous factor H deficiency.
        Clin Exp Nephrol Case Rep. 2013;
        • Vogt B.A.
        • Wyatt R.J.
        • Burke B.A.
        • Simonton S.C.
        • Kashtan C.E.
        Inherited factor H deficiency and collagen type III glomerulopathy.
        Pediatr Nephrol. 1995; 9: 11-15
        • Ault B.H.
        • Schmidt B.Z.
        • Fowler N.L.
        • Kashtan C.E.
        • Ahmed A.E.
        • Vogt B.A.
        • et al.
        Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism.
        J Biol Chem. 1997; 272: 25168-25175
        • Schmidt B.Z.
        • Fowler N.L.
        • Hidvegi T.
        • Perlmutter D.H.
        • Colten H.R.
        Disruption of disulfide bonds is responsible for impaired secretion in human complement factor H deficiency.
        J Biol Chem. 1999; 274: 11782-11788
        • Schejbel L.
        • Schmidt I.M.
        • Kirchhoff M.
        • Andersen C.B.
        • Marquart H.V.
        • Zipfel P.
        • et al.
        Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation.
        Genes Immun. 2011; 12: 90-99
        • Wilson V.
        • Darlay R.
        • Wong W.
        • Wood K.M.
        • McFarlane J.
        • Schejbel L.
        • et al.
        Genotype/phenotype correlations in complement factor h deficiency arising from uniparental isodisomy.
        Am J Kidney Dis. 2013; (In press)
        • Licht C.
        • Heinen S.
        • Józsi M.
        • Loschmann I.
        • Saunders R.E.
        • Perkins S.J.
        • et al.
        Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II).
        Kidney Int. 2006; 70: 42-50
        • Habbig S.
        • Mihatsch M.J.
        • Heinen S.
        • Beck B.
        • Emmel M.
        • Skerka C.
        • et al.
        C3 deposition glomerulopathy due to a functional factor H defect.
        Kidney Int. 2009; 75: 1230-1234
        • Martínez-Barricarte R.
        • Heurich M.
        • Valdes-Cañedo F.
        • Vazquez-Martul E.
        • Torreira E.
        • Montes T.
        • 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: 3702-3712
        • Athanasiou Y.
        • Voskarides K.
        • Gale D.P.
        • Damianou L.
        • Patsias C.
        • Zavros M.
        • et al.
        Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees.
        Clin J Am Soc Nephrol. 2011; 6: 1436-1446
        • Neary J.
        • Dorman A.
        • Campbell E.
        • Keogan M.
        • Conlon P.
        Familial membranoproliferative glomerulonephritis type III.
        Am J Kidney Dis. 2002; 40: E1
        • Neary J.J.
        • Conlon P.J.
        • Croke D.
        • Dorman A.
        • Keogan M.
        • Zhang F.Y.
        • et al.
        Linkage of a gene causing familial membranoproliferative glomerulonephritis type III to chromosome 1.
        J Am Soc Nephrol. 2002; 13: 2052-2057
        • Malik T.H.
        • Lavin P.J.
        • Goicoechea de Jorge E.
        • Vernon K.A.
        • Rose K.L.
        • Patel M.P.
        • et al.
        A hybrid CFHR3-1 gene causes familial C3 glomerulopathy.
        J Am Soc Nephrol. 2012; 23: 1155-1160
        • Berry P.L.
        • McEnery P.T.
        • McAdams A.J.
        • West C.D.
        Membranoproliferative glomerulonephritis in two sibships.
        Clin Nephrol. 1981; 16: 101-106
        • Marder H.K.
        • Coleman T.H.
        • Forristal J.
        • Beischel L.
        • West C.D.
        An inherited defect in the C3 convertase, C3b, Bb, associated with glomerulonephritis.
        Kidney Int. 1983; 23: 749-758
        • Linshaw M.A.
        • Stapleton F.B.
        • Cuppage F.E.
        • Forristal J.
        • West C.D.
        • Schreiber R.D.
        • et al.
        Hypocomplementemic glomerulonephritis in an infant and mother. Evidence for an abnormal form of C3.
        Am J Nephrol. 1987; 7: 470-477
        • Lopez-Larrea C.
        • Dieguez M.
        • Enguix A.
        • Dominguez O.
        • Marín B.
        • Gomez E.
        A familial deficiency of complement factor H.
        Biochem Soc Trans. 1987; 15: 648-649
        • Herrin J.T.
        • Bartsocas C.S.
        Familial membranoproliferative glomerulonephritis type 2 (MPGN-2).
        Prog Clin Biol Res. 1989; 305: 161-166
        • Power D.A.
        • Ng Y.C.
        • Simpson J.G.
        Familial incidence of C3 nephritic factor, partial lipodystrophy and membranoproliferative glomerulonephritis.
        QJM. 1990; 75: 387-398
        • López-Trascasa M.
        • Martín-Villa J.M.
        • Vicario J.L.
        • Marín M.A.
        • Martínez-Ara J.
        • García-Messeguer M.C.
        • et al.
        Familial incidence of C3 nephritic factor.
        Nephron. 1991; 59: 261-265
        • Motoyama O.
        • Sakai K.
        • Ohashi Y.
        • Mizuiri S.
        • Hatori T.
        • Iitaka K.
        • et al.
        Membranoproliferative glomerulonephritis in a girl and her mother.
        Clin Exp Nephrol. 2009; 13: 77-80
        • Hageman G.S.
        • Hancox L.S.
        • Taiber A.J.
        • Gehrs K.M.
        • Anderson D.H.
        • Johnson L.V.
        • et al.
        Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications.
        Ann Med. 2006; 38: 592-604
        • Goicoechea de Jorge E.
        • Caesar J.J.
        • Malik T.H.
        • Patel M.
        • Colledge M.
        • Johnson S.
        • et al.
        Dimerization of complement factor H-related proteins modulates complement activation in vivo.
        Proc Natl Acad Sci U S A. 2013; 110: 4685-4690
        • Hughes A.E.
        • Orr N.
        • Esfandiary H.
        • Diaz-Torres M.
        • Goodship T.
        • Chakravarthy U.
        A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration.
        Nat Genet. 2006; 38: 1173-1177
        • Gharavi A.G.
        • Kiryluk K.
        • Choi M.
        • Li Y.
        • Hou P.
        • Xie J.
        • et al.
        Genome-wide association study identifies susceptibility loci for IgA nephropathy.
        Nat Genet. 2011; 43: 321-327
        • Servais A.
        • Noël L.H.
        • Dragon-Durey M.A.
        • Gubler M.C.
        • Remy P.
        • Buob D.
        • et al.
        Heterogeneous pattern of renal disease associated with homozygous factor H deficiency.
        Hum Pathol. 2011; 42: 1305-1311
        • Vaziri-Sani F.
        • Holmberg L.
        • Sjoholm A.G.
        • Kristoffersson A.C.
        • Manea M.
        • Frémeaux-Bacchi V.
        • et al.
        Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome.
        Kidney Int. 2006; 69: 981-988
        • Alper C.A.
        • Abramson N.
        • Johnston Jr, R.B.
        • Jandl J.H.
        • Rosen F.S.
        Increased susceptibility to infection associated with abnormalities of complement-mediated functions and of the third component of complement (C3).
        N Engl J Med. 1970; 282: 350-354
        • Abrera-Abeleda M.A.
        • Nishimura C.
        • Frees K.
        • Jones M.
        • Maga T.
        • Katz L.M.
        • et al.
        Allelic variants of complement genes associated with dense deposit disease.
        J Am Soc Nephrol. 2011; 22: 1551-1559
        • Pickering M.C.
        • Goicoechea de Jorge E.
        • Martínez-Barricarte R.
        • Recalde S.
        • Garcia-Layana A.
        • Rose K.L.
        • et al.
        Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains.
        J Exp Med. 2007; 204: 1249-1256
        • Heurich M.
        • Martínez-Barricarte R.
        • Francis N.J.
        • Roberts D.L.
        • Rodríguez de Córdoba S.
        • Morgan B.P.
        • et al.
        Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk.
        Proc Natl Acad Sci U S A. 2011; 108: 8761-8766
        • Hageman G.S.
        • Anderson D.H.
        • Johnson L.V.
        • Hancox L.S.
        • Taiber A.J.
        • Hardisty L.I.
        • et al.
        A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.
        Proc Natl Acad Sci U S A. 2005; 102: 7227-7232
        • Clark S.J.
        • Ridge L.A.
        • Herbert A.P.
        • Hakobyan S.
        • Mulloy B.
        • Lennon R.
        • et al.
        Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions.
        J Immunol. 2013; 190: 2049-2057
        • Montes T.
        • Goicoechea de Jorge E.
        • Ramos R.
        • Gomà M.
        • Pujol O.
        • Sánchez-Corral P.
        • et al.
        Genetic deficiency of complement factor H in a patient with age-related macular degeneration and membranoproliferative glomerulonephritis.
        Mol Immunol. 2008; 45: 2897-2904
        • Hegasy G.A.
        • Manuelian T.
        • Høgåsen K.
        • Jansen J.H.
        • Zipfel P.F.
        The molecular basis for hereditary porcine membranoproliferative glomerulonephritis type II: point mutations in the factor H coding sequence block protein secretion.
        Am J Pathol. 2002; 161: 2027-2034
        • Pickering M.C.
        • Cook H.T.
        • Warren J.
        • Bygrave A.E.
        • Moss J.
        • Walport M.J.
        • et al.
        Uncontrolled C3 activation causes membranoproliferative glomerulonephritis in mice deficient in complement factor H.
        Nat Genet. 2002; 31: 424-428
        • Pickering M.C.
        • Warren J.
        • Rose K.L.
        • Carlucci F.
        • Wang Y.
        • Walport M.J.
        • et al.
        Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice.
        Proc Natl Acad Sci U S A. 2006; 103: 9649-9654
        • Rose K.L.
        • Paixão-Cavalcante D.
        • Fish J.
        • Manderson A.P.
        • Malik T.H.
        • Bygrave A.E.
        • et al.
        Factor I is required for the development of membranoproliferative glomerulonephritis in factor H-deficient mice.
        J Clin Invest. 2008; 118: 608-618
        • Paixão-Cavalcante D.
        • Hanson S.
        • Botto M.
        • Cook H.T.
        • Pickering M.C.
        Factor H facilitates the clearance of GBM bound iC3b by controlling C3 activation in fluid phase.
        Mol Immunol. 2009; 46: 1942-1950
        • Fakhouri F.
        • Goicoechea de Jorge E.
        • Brune F.
        • Azam P.
        • Cook H.T.
        • Pickering M.C.
        Treatment with human complement factor H rapidly reverses renal complement deposition in factor H-deficient mice.
        Kidney Int. 2010; 78: 279-286
        • Jansen J.H.
        • Høgåsen K.
        • Harboe M.
        • Hovig T.
        In situ complement activation in porcine membranoproliferative glomerulonephritis type II.
        Kidney Int. 1998; 53: 331-349
        • Vyse T.J.
        • Spath P.J.
        • Davies K.A.
        • Morley B.J.
        • Philippe P.
        • Athanassiou P.
        • et al.
        Hereditary complement factor I deficiency.
        QJM. 1994; 87: 385-401
        • Ruseva M.M.
        • Vernon K.A.
        • Lesher A.M.
        • Schwaeble W.J.
        • Ali Y.M.
        • Botto M.
        • et al.
        Loss of properdin exacerbates c3 glomerulopathy resulting from factor h deficiency.
        J Am Soc Nephrol. 2013; 24: 43-52
        • Lesher A.M.
        • Zhou L.
        • Kimura Y.
        • Sato S.
        • Gullipalli D.
        • Herbert A.P.
        • et al.
        Combination of factor H mutation and properdin deficiency causes severe C3 glomerulonephritis.
        J Am Soc Nephrol. 2013; 24: 53-65
        • Goicoechea de Jorge E.
        • Macor O.
        • Paixão-Cavalcante D.
        • Rose K.L.
        • Tedesco F.
        • Cook H.T.
        • et al.
        The development of atypical hemolytic uremic syndrome depends on complement C5.
        J Am Soc Nephrol. 2011; 22: 137-145
        • Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group
        KDIGO Clinical Practice Guideline for Glomerulonephritis. General principles in the management of glomerular disease.
        Kidney Int Suppl. 2012; 2: 156-162
        • McEnery P.T.
        • McAdams A.J.
        Regression of membranoproliferative glomerulonephritis type II (dense deposit disease): observations in six children.
        Am J Kidney Dis. 1988; 12: 138-146
        • Tarshish P.
        • Bernstein J.
        • Tobin J.N.
        • Edelmann Jr., C.M.
        Treatment of mesangiocapillary glomerulonephritis with alternate-day prednisone--a report of the International Study of Kidney Disease in Children.
        Pediatr Nephrol. 1992; 6: 123-130
        • Marks S.D.
        • Rees L.
        Spontaneous clinical improvement in dense deposit disease.
        Pediatr Nephrol. 2000; 14: 322-324
        • Ikeda M.
        • Honda M.
        • Hasegawa O.
        Another example of spontaneous improvement in a case of dense deposit disease.
        Pediatr Nephrol. 2001; 16: 609-610
        • West C.D.
        • McAdams A.J.
        • Witte D.P.
        Acute non-proliferative glomerulitis: a cause of renal failure unique to children.
        Pediatr Nephrol. 2000; 14: 786-793
        • Barbour T.
        • Johnson S.
        • Cohney S.
        • Hughes P.
        Thrombotic microangiopathy and associated renal disorders.
        Nephrol Dial Transplant. 2012; 27: 2673-2685
        • Kurtz K.A.
        • Schlueter A.J.
        Management of membranoproliferative glomerulonephritis type II with plasmapheresis.
        J Clin Apher. 2002; 17: 135-137