Membranoproliferative Glomerulonephritis Type II (Dense Deposit Disease): An Update
Gerald B. Appel*,
H. Terence Cook,
Gregory Hageman,
J. Charles Jennette,
Michael Kashgarian||,
Michael Kirschfink¶,
John D. Lambris#,
Lynne Lanning**,
Hans U. Lutz,
Seppo Meri,
Noel R. Rose,
David J. Salant||||,
Sanjeev Sethi¶¶,
Richard J.H. Smith##,
William Smoyer***,
Hope F. Tully,
Sean P. Tully,
Patrick Walker,
Michael Welsh,
Reinhard Würzner|||||| and
Peter F. Zipfel¶¶¶
* Columbia University Department of Nephrology, New York, New York; Division of Investigative Science, Imperial College Faculty of Medicine, London, England; Department of Ophthalmology and Visual Sciences, University of Iowa, Carver College of Medicine, Iowa City, Iowa; Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina; || Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; ¶ Institute of Immunology, University of Heidelberg, Heidelberg, Germany; # Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; ** Kidneeds, Iowa City, Iowa; Institute of Biochemistry, Swiss Federal Institute of Technology, Zurich, Switzerland; Department of Bacteriology and Immunology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Center for Autoimmune Disease Research, Johns Hopkins School of Medicine, Baltimore, Maryland; |||| Department of Medicine, Boston University Medical Center, Boston, Massachusetts; ¶¶ Department of Pathology, University of Iowa, Carver ## Department of Otolaryngology, University of Iowa Carver College of Medicine, Iowa City, Iowa; *** Pediatric Nephrology Division, University of Michigan, Ann Arbor, Michigan; Milagros Research Fund, Chappaqua, New York, New York; Nephropathology Associates, Little Rock, Arkansas; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa; |||||| Department of Hygiene, Microbiology and Social Medicine, Innsbruck Medical University, Innsbruck, Austria; and ¶¶¶ Hans Knoell Institute for Natural Products Research, Jena, Germany
Address correspondence to: Dr. Richard J.H. Smith, Department of Otolaryngology, 200 Hawkins Drive, 21151 PFP, The University of Iowa, Iowa City, IA 52242. Phone: 319-356-3612; Fax: 319-356-4108; richard-smith{at}uiowa.edu
Membranoproliferative glomerulonephritis type II (MPGN II) isa rare disease characterized by the deposition of abnormal electron-densematerial within the glomerular basement membrane of the kidneyand often within Bruch’s membrane in the eye. The diagnosisis made in most patients between the ages of 5 and 15 yr, andwithin 10 yr, approximately half progress to end-stage renaldisease, occasionally with the late comorbidity of visual impairment.The pathophysiologic basis of MPGN II is associated with theuncontrolled systemic activation of the alternative pathway(AP) of the complement cascade. In most patients, loss of complementregulation is caused by C3 nephritic factor, an autoantibodydirected against the C3 convertase of the AP, but in some patients,mutations in the factor H gene have been identified. For thelatter patients, plasma replacement therapy prevents renal failure,but for the majority of patients, there is no proven effectivetreatment. The disease recurs in virtually all renal allografts,and a high percentage of these ultimately fail. The developmentof molecular diagnostic tools and new therapies directed atcontrolling the AP of the complement cascade either locallyin the kidney or at the systemic level may lead to effectivetreatments for MPGN II.
The membranoproliferative glomerulonephritides are diseasesof diverse and often obscure cause and pathogenetic mechanismsthat account for approximately 4 and 7% of primary renal causesof nephrotic syndrome in children and adults, respectively (1).On the basis of immunopathology and ultrastructure analysisof the kidney and of the glomerulus in particular, three subtypesare recognized. Membranoproliferative glomerulonephritis (MPGN)types I and III are variants of immune complex-mediated disease;MPGN II, in contrast, has no known association with immune complexes.
MPGN II is rare. It accounts for <20% of cases of MPGN inchildren and only a fractional percentage of cases in adults(2). Its morphologic hallmark is the presence of dense depositswithin the glomerular basement membrane (GBM) as resolved byelectron microscopy. In many individuals with MPGN II, depositsof similar composition and structure occur along the choriocapillaris-Bruch’smembrane-retinal pigment epithelial interface, a region thatis morphologically similar to the capillary tuft-GBM-glomerularepithelial interface (Figure 1). Spontaneous remissions arerare, and most affected individuals progress to end-stage renaldisease (ESRD), occasionally with the late comorbidity of impairedvisual acuity and fields (3–13).
Figure 1. Schematic drawings that compare the fenestrated capillary networks in the glomerulus (A) and retina (B). The glomerular podocytes are similar to the retinal pigment epithelial cells, both of which are separated by a basement membrane (either the glomerular basement membrane [GBM]or Bruch’s membrane, respectively) from the fenestrated capillary endothelial cells of the glomerular capillary tufts and the choriocapillaris. Both basement membranes are sites of electron-dense deposits in membranoproliferative glomerulonephritis type II (MPGN II).
The purpose of this article is to summarize the proceedingsof the first meeting of the international MPGN II Focus Group.We provide a comprehensive review of the clinical, histopathologic,and pathophysiologic features of MPGN II, focusing on the roleof complement and complement dysregulation in the pathogenesisof this disease so that effective evidence-based treatmentsmay be developed.
MPGN II affects both genders equally and is usually diagnosedin children who are between 5 and 15 yr of age and present withone of five findings: Hematuria, proteinuria, hematuria andproteinuria, acute nephritic syndrome, or nephrotic syndrome.Although these findings are nonspecific, >80% of patientswith MPGN II are positive for serum C3 nephritic factor (C3NeF),an autoantibody directed against C3bBb, the convertase of thealternative pathway (AP) of the complement cascade (14). BecauseC3NeF is present in up to one half of people with MPGN typesI and III, the definitive diagnosis of MPGN II depends on theultrastructural demonstration of dense deposits in the GBM.
Patients with MPGN II can develop drusen (Figure 2). These whitish-yellowdeposits lie within the ocular Bruch’s membrane, beneaththe retinal pigment epithelium. In contrast to drusen that formin age-related macular degeneration, drusen in individuals withMPGN II occur at an early age and often are detectable in thesecond decade of life. The distribution of these deposits variesamong patients (4,15,16) and initially has little impact onvisual acuity and fields. Over time, however, specialized testsof retinal function, such as dark adaptation, electroretinography,and electrooculography, can become abnormal. Vision can deteriorateas subretinal neovascular membranes, macular detachment, andcentral serous retinopathy develop (4). The long-term risk forvisual problems is approximately 10%. There is no correlationbetween disease severity in the kidney and the eye, and an ophthalmologicexamination at the time of diagnosis and periodic funduscopicassessments should be part of patient treatment (17).
Figure 2. A funduscopic picture of MPGN II–associated retinal changes (A) as compared with a normal retina (B). The long-term risk for visual problems caused by drusen in MPGN II is approximately 10%. There is no correlation between disease severity in the kidney and the eye.
MPGN II can be associated with acquired partial lipodystrophy(APL) (18). The loss of subcutaneous fat in the upper half ofthe body usually precedes the onset of kidney disease by severalyears and can result in a strikingly haggard facial appearance.Misra et al. (19) reported that approximately 83% of APL patientshave low C3 levels and polyclonal C3NeF and that approximately20% go on to develop MPGN after a median of approximately 8yr after the onset of lipodystrophy. Compared with APL patientswithout renal disease, those with MPGN have an earlier age ofonset of lipodystrophy (12.6 ± 10.3 versus 7.7 ±4.4 yr, respectively; P < 0.001) and a higher prevalenceof C3 hypocomplementemia (78 versus 95%, respectively; P = 0.02).The link between these two entities seems to be related to theeffects of dysregulation of the AP of the complement cascadeon both kidney and adipose tissue (20). The deposition of activatedcomponents of complement in adipose tissue results in the destructionof adipocytes in areas high in factor D (fD; adipsin) content.
Spontaneous remissions of MPGN II are uncommon (2,21). The moreprobable outcome is chronic deterioration of renal functionleading to ESRD in approximately half of patients within 10yr of diagnosis (22–25). In some patients, rapid fluctuationsin proteinuria occur with episodes of acute renal deteriorationin the absence of obvious triggering events; in others, thedisease remains stable for years despite persistent proteinuria.
In >50% of patients with MPGN II, serum C3NeF persists throughoutthe disease course (14). C3NeF is nearly always associated withclinical evidence of complement activation such as a reductionin CH50, a decrease in C3, and an increase in C3dg/C3d; however,the relationship among C3NeF, C3 levels, and prognosis is unclear.Some groups report no correlation between C3 levels and clinicalcourse (18,24,26,27), whereas other groups have found persistenthypocomplementemia indicative of a poor prognosis (28,29).
These differences may be reconciled by noting that not all C3NeFare directed against the same epitope and that epitopes canchange in an individual over time. Ohi et al. (30) providedevidence for the first possibility in their report of six patientswith detectable C3NeF in the absence of hypocomplementemia,showing that in these cases, C3NeF did not interfere with factorH (fH)-induced inactivation of C3bBb. Spitzer and Stitzel (31)documented the second possibility in three people whose C3 levelseventually normalized despite continued C3NeF production. C3NeFisolated from these patients and added to normal sera mediatedconsumption of C3, as did the addition of normal factor B (fB)to their sera, consistent with a change in the fB autoantigenin these patients.
The term membranoproliferative glomerulonephritis is a histologicreference to the thickening of capillary walls, intense glomerularhypercellularity, and increased amounts of mesangial matrixthat are usually apparent at the light microscopic level (Figure 3).However, it is the dense intramembranous deposits in theGBM that are the pathognomonic feature of MPGN II (Figure 4).In fact, dense deposit disease is a more accurate descriptivename than MPGN II because dense deposits are diagnostic andare not invariably associated with prominent capillary wallthickening or hypercellularity (Figure 3A).
Figure 3. The light microscopic appearance of MPGN II varies from mild mesangial hypercellularity (A) through a membranoproliferative pattern (B) to crescent glomerulonephritis (C). C3 is present in an interrupted band pattern along GBM, tubular basement membranes, and the basement membranes of Bowman’s capsule (D). C3 in the mesangial areas can result in a prominent spherule or "ring" like pattern (E). Along tubular basement membranes, C3 is present in an interrupted pattern (F). Magnification, x400 (periodic acid-Schiff stain) in A through C; x200 (fluorescein-conjugated anti-C3) in D; x400 (fluorescein-conjugated anti-C3) in E and F; x1000 (fluorescein-conjugated anti-C3) in E inset.
Figure 4. Electron microscopy reveals an interrupted band pattern of extremely electron-dense material (arrows) along the capillary walls and paramesangial GBM (A). Electron-dense material (arrows) in the mesangial areas sometimes appears as spheres (B). Electron-dense material forming masses with open areas within the mesangial region may correspond to mesangial "rings" seen by immunofluorescence (C; see Figure 3E). Electron-dense material extending from the mesangium into the capillary loop with the basement membrane on either side produces a "tram-track" pattern (D). It is intriguing to speculate that these dense deposits may be the result of continuous complement activation (see Figure 6). Magnification, x4000 (uranyl acetate and lead citrate) in A; x10,000 (uranyl acetate and lead citrate) in B; x7500 (uranyl acetate and lead citrate) in C; x15,000 (uranyl acetate and lead citrate) in D.
The normal GBM is built from a three-dimensional scaffold oftype IV collagen in the lamina densa and provides mechanicalstability, a framework for proteoglycans and glycoproteins,and a size-selective filtration barrier to plasma proteins >150kD (1,32,33). Core proteins and glycosaminoglycans (GAG) concentratein a regular lattice-like network on either side of the laminadensa in the laminae rarae internae and externae and give theGBM its negative charge. Most abundant is heparan sulfate, whichcontributes approximately 90% of the negative charge of theGBM. It promotes hydration, prevents obstruction, and acts asa charge-selective barrier to small polyanionic plasma proteinsof 70 to 150 kD in size (1,33).
The dense deposits associated with MPGN II are distributed ina segmental, discontinuous, or diffuse pattern in the laminadensa of the GBM. By light microscopy, they are eosinophilicand refractile, stain brightly with periodic acid-Schiff, andare highly osmophilic, explaining their electron-dense appearance(32) (Figure 4). Even at high magnification, the deposits lacksubstructure and appear as a very dark homogeneous smudge. Often,they are present in the mesangial matrix, along the basementmembranes of Bowman’s capsule, and around small vessels.They also stain brightly with thioflavine-T and wheat germ agglutinin(32,34), suggesting the presence of large amounts of N-acetyl-glucosamine.As compared with normal GBM, there are distinct differencesin amino acid and carbohydrate composition in dense depositswith decreased and increased cysteine and N-acetyl-neuraminicacid levels, respectively (P < 0.01 for both) (35). Still,the exact composition of dense deposits remains undetermined.
Mesangial hypercellularity and matrix interposition occur asthe disease progresses, with the degree of involvement rangingfrom minimal to diffuse among different glomeruli even withinthe same biopsy specimen (36). Podocyte changes also develop,perhaps reflecting either an interference with podocyte-GBM-mesangialcell cross-talk or changes in the negative surface charge onpodocytes (37). Although major causes of podocyte injury leadingto ESRD include perturbation of the actin cytoskeleton and interferencewith the slit diaphragm-lipid raft complex, these two eventsare not thought to be central to the progression of MPGN II.If early damage is not reversed, then severe and progressivechanges develop in the GBM, ultimately leading to podocyte detachment,hypertrophy, and death (38).
The characteristic immunopathologic finding in MPGN II is intensedeposition of C3 along the glomerular capillary walls in a ribbon-likepattern and in the mesangial regions as coarse granules or spherules.Often, a double contour linear "railroad track" is apparentalong capillary walls with a "ring" forming around mesangialdeposits as if only the outer surface of the deposits is staining.More specific immunohistology has shown that C3c is the primaryconstituent of dense deposits in many patients with MPGN II;however, in patients with rapidly progressive MPGN II, densedeposits react with anti-C3d antibodies as well as anti-C3cantibodies. This difference suggests the presence of both C3band iC3b in patients with rapidly progressive disease, becauseall C3 breakdown products except C3c react with anti-C3d. Notablyabsent from dense deposits and other regions of the glomerulusare deposits of IgG, suggesting that C3NeF is not a constituentof dense deposits and that dense deposits do not represent depositionof immune complexes (38) (Figures 3 and 5). Similar depositsare seen in Bruch’s membrane in the eye and in the sinusoidalbasement membranes of the spleen (4,15–17,39).
Figure 5. Native C3 consists of two chains joined by a disulfide bond. Activation by C3 convertase cleaves off C3a, an anaphylatoxin, to form C3b. Because C3 is cleaved into many fragments, immunostaining can be done using antibodies to different breakdown products of C3. In many patients with MPGN II, only immunostaining with anti-C3c antibodies is positive; however, in patients with rapidly progressive MPGN II, dense deposits also are recognized by anti-C3d antibodies, suggesting the presence of C3b and iC3b. IgG is absent.
The complement system is a complex cascade in which proteolyticcleavage of glycoproteins induces an inflammatory response,phagocyte chemotaxis, opsonization, and cell lysis. It is triggeredthrough three different pathways—the classical, alternative,or mannose-binding lectin—that converge on C3 to ultimatelyform the membrane attack complex, C5b678 (9). In MPGN II, thealternative pathway (AP) is systematically activated at a highlevel.
C3 is the most abundant complement protein in serum (1.2 mg/ml).It normally undergoes low levels of continuous autoactivationby hydrolysis of its thioester. Hydrolyzed C3 (C3[H2O]) bindsfB to form C3(H2O)B, which after cleavage to C3(H2O)Bb by fDcleaves C3 to C3a and C3b. C3b recruits fB and fD releases Bato generate C3bBb, the C3 convertase of the AP. The amplifyingconvertase produces nascent C3b by way of a fleeting intermediatethat reacts with water, hydroxyl groups on complex carbohydrates,cell surfaces, immune complexes, and free IgG within a radiusof approximately 60 nm from the point of its generation (40).
Nascent C3b that reacts with water forms free C3b that has ahalf-life of <1 s in the presence of fH and fI in the fluidphase. However, nascent C3b that binds covalently to large moleculesis partially protected from inactivation. Because IgG is thesecond most abundant protein in plasma and C3 has a weak affinityfor IgG, during systemic activation of the complement cascadein the fluid phase, nascent C3b reacts predominantly with IgGto produce (C3b)2-IgG complexes (41). (C3b)2-IgG complexes arefar better precursors of the C3 convertase of the AP than freeC3b because in addition to being protected from inactivationby fH, they are intrinsically more potent than C3b in assemblinga C3 convertase, presumably because they first bind properdin,which facilitates fB binding (42,43) (Figures 5 and 6).
Figure 6. The alternative pathway of the complement cascade is systematically activated at a high level in patients with MPGN II. Normally, continuous low levels of activation of C3 occur by spontaneous hydrolysis. Hydrolysis causes a large conformational change in C3 to make C3(H20) more similar to C3b, although C3a is still attached. The initial convertase, C3(H2O)Bb, activates C3 to C3b. C3b has a fleeting half-life, but if it binds to IgG, cells, or basement membranes, then it is somewhat protected from immediate inactivation. C3 has a weak affinity for IgG and so (C3b)2-IgG complexes form in the fluid phase. These complexes bind properdin (P), which facilitates factor B (fB) binding and generation of the C3 convertase of the alternative pathway (red arrows, amplification loop). C3NeF (inset) prolongs the half-life of C3 convertase by binding to a neo-epitope on either C3bBb or Bb. In the mouse mutant deficient for both factor H (fH) and fB, C3bBb cannot form, so activation of the alternative pathway of the complement cascade does not occur.
In MPGN II, C3NeF prolongs the half-life of C3 convertase bybinding to either C3bBb or IgG-C3b-C3bBb of the assembled convertase.C3NeF slows down dissociation of factor Bb from the C3 convertaseprecursor, and as a result, this neoenzyme can interact withits substrates for a longer period of time. The exact mechanismby which this stabilization occurs is unknown and may vary amongpatients, consistent with suspected differences in C3NeF itself.
The normal protective and regulatory mechanisms that controlC3bBb levels and complement complex deposition on self-cellsinvolve seven proteins. Four of these proteins are present inthe serum (fH, factor H-like protein 1 [FHL-1], factor I [fI],and C4 binding protein [C4BP]), and three are cell membrane-associatedproteins (membrane co-factor protein [MCP, CD46], decay acceleratingfactor [DAF, CD55], and complement receptor 1 [CR1, CD35]).With the exception of fI, these proteins belong to the regulators-of-complement-activation(RCA) family of proteins on chromosome 1q32. A striking structuralfeature shared by the RCA family is homologous 60–aminoacid domains known as short consensus repeats (SCR). CR1 has30, fH has 20, FHL-1 has seven, and CD55 has four of these domains(44).
fH is a soluble glycoprotein present in blood at concentrationsranging from 110 to 615 µg/ml. It regulates complementboth in fluid phase and on cellular surfaces by binding to threesites on C3b destabilizing C3bBb. In fluid phase, this interactionresults in dissociation of C3bBb into inactive fBb (ifBb) andC3bfH, which is irreversibly inactivated into iC3b by fI (45).On surfaces, the inactivation of bound C3b is dependent on thechemical composition of the surface to which C3b is bound (46).
Binding of C3bBb by C3NeF makes this complex far more resistantto fH-mediated inactivation than properdin-stabilized convertase(40,47). iC3b that does form can bind to CR1, a polymorphicmembrane protein of 190 to 280 kD present on most peripheralcells. CR1 on erythrocytes accounts for almost 90% of the regulatorin blood (48). Approximately 15% of healthy people have lowCR1 erythrocyte levels, and in a few people, levels are extremelylow (49,50). Whether there is an association with this variabilityand MPGN II is not known. CR1 is also expressed on podocytes,where its biologic function remains speculative. A loss of CR1on podocytes has been found in various nephropathies, includingsevere lupus nephritis and crescentic nephritis, and its releaseas CR1-coated vesicles in the urine is considered a marker ofpodocyte injury (51). Cleavage fragments of C3b such as C3cand C3dg are found in the plasma of patients with MPGN II (Figure 5).
fH also binds to polyanions, such as heparin on cells and membranes,and protects these surfaces from AP-mediated complement activation(52). This discriminatory activity of fH is dependent on specificSCR, which recognize sialic acid and other negatively chargedGAG (Figure 7). The importance of this protective role is highlightedby the fact that MPGN II develops in humans, pigs, and micethat are deficient in fH (36,53–55).
Figure 7. The fH family of proteins contains six members that localize to the regulators-of-complement-activation (RCA) region on 1q32. The functions of some short consensus repeats (SCR) are not known. FHL1 is a splice variant of fH. Each SCR in the fH-related proteins has some (often low) homology to an SCR in fH, as indicated by the number in the ovals. CRP, C-reactive protein; Hep, heparin.
In addition to fH, there are five other members of this proteinfamily, although their functional properties have not been definedfully. fH-related protein 3 (FHR3), two forms of FHR4 termedFHR4A and FHR4B, and FHR5 bind C3b; however, as these proteinsdo not have SCR homologous to functionally active fH domains,they do not have detectable decay accelerating or fI co-factoractivity (46,56). Possibly most interesting with respect toMPGN II is FHR5, which is present in pathologic glomeruli fromindividuals with kidney disease (57). Its expression has beendocumented in podocytes and in in vitro studies FHR5 has beenshown to associate with surfaces exposed to complement attackwith subsequent binding of C3b, suggesting a probable role relatedto complement activation. The precise relationship between FHR5and MPGN II has not been defined.
The few patients with inherited mutations of fH and MPGN IIhave provided valuable insight into disease pathogenesis. Onepatient, a 13-mo-old Native American, segregated a C518R mutationin fH SCR9 in trans with a C941Y mutation in fH SCR16, the resultbeing retention of fH in the endoplasmic reticulum (55). Twobrothers homozygous for R127L in fH SCR2 also developed an MPGNII–like disease (54).
The relationship between fH function and MPGN II has been exploredin detail in animals. Norwegian Yorkshire pigs that segregatean I1166R mutation in SCR20 develop MPGN II and die within 7wk of birth. The I1166R mutation prevents extracellular releaseof fH, which accumulates intracellularly in disease animalsand results in uncontrolled complement activation (36,58). Glomerulardisease as evidenced by deposition of complement actually beginsin utero with C3 and terminal complement complex co-depositionin the GBM. The GBM serves as the nidus of complement activationbecause it lacks membrane-bound RCA proteins. Morphologic evidenceof glomerulonephritis develops later.
The fH-deficient pig model is no longer available (althoughsperm has been stored), but a mouse with a targeted deletionof fH has been made. Plasma concentrations of C3 in the fH–/–mouse are significantly reduced, with most plasma C3 convertedto C3b (53). Heterozygous mouse mutants (fH+/–) also havedepressed levels of C3, suggesting that haploinsufficiency impairsnormal C3bBb control mechanisms. Unlike the fH-deficient pig,the fH-deficient mouse has only a 25% 8-mo mortality, but inconcordance with the pig model, MPGN develops in all mice andC3 deposition on glomerular capillary walls also precedes thedevelopment of glomerulonephritis. It is interesting that theglomeruli are the only site of C3 deposition in these mice,suggesting that the GBM has a unique requirement for the protectiverole of fH. The mouse mutant null for both fH and fB (fH–/–;fB–/–) has a normal renal phenotype (53). The absenceof fB in these animals prevents the formation of C3bBb and therebyprecludes activation of the AP of complement, making the absenceof fH inconsequential.
The central role of tight C3bBb regulation in the preventionof MPGN II is supported by the report of a 57-yr-old woman whodeveloped renal insufficiency and by histopathologic and electronicmicroscopic analysis of the kidney had both subendothelial andintramembranous dense deposits consistent with MPGN types Iand II. Serum C3 and fB levels were reduced, and when patientserum was mixed with control serum, dose-dependent activationof the AP of the complement cascade was observed. A mini-autoantibodyin the form of a monoclonal Ig light chain dimer was identifiedthat bound to the SCR3 of fH and the anionic GBM, causing vigorousAP activation and C3 overconsumption (59).
These animal and human data provide compelling evidence thatthe uncontrolled systemic activation of the AP of the complementcascade results in MPGN II. The initiating triggers can differ,suggesting that the causes of MPGN II are heterogeneous. Somepatients develop MPGN II secondary to mutations in fH or toautoantibodies that impede fH function (54,55,58), but in mostpatients, complement dysregulation is the consequence of theC3NeF autoantibody, which usually binds to C3bBb protectingit from fH-mediated inactivation (46,60).
Because most patients with MPGN II develop complement dysregulationassociated with the presence of C3NeF, the appearance of thisautoantibody is particularly germane to understanding the pathogenesisof this disease. It is now well recognized that healthy individualscan have autoantibodies associated with many different autoimmunedisorders, although titers and prevalence of these autoantibodiesare typically very low (61–63). It has been proposed thatan idiotype network may regulate this expression and that criticalself-epitopes are key to the understanding of self-toleranceand autoimmunity (64–66).
On the basis of Jerne’s theory of the idiotypic network,immunization with an antigen leads to a cascade of responses(64). The initial response involves the generation of the antigen-specificantibody (Ab1), which has a unique antigenic site within itsvariable region to recognize the immunizing antigen. However,this unique site itself can elicit an antibody response. Thesecond antibody, Ab2, is an anti-idiotypic antibody becausethe antigenic site that it recognizes is the variable regionor idiotype of Ab1. Ab2 in turn induces Ab3 as an anti-anti-idiotyperesponse, and so on. Because Ab2 recognizes Ab1 and Ab3 recognizesAb2, Ab3 and Ab1 often have similar binding capacities (67,68).
Consistent with Jerne’s idiotype network theory, bothhigh-affinity C3NeF antibodies (Ab1) and anti-idiotypic antibodiesto C3NeF (Ab2) can be identified in newborns and normal adults(69,70). Anti-idiotypic antibodies to C3NeF (Ab2) can also bepurified from normal and patient sera (71). The inciting eventsthat can lead to dysregulation of this idiotype network in patientswith MPGN II are unknown.
At this time, there is no universally effective treatment forMPGN II (72–74). Numerous therapeutic regimens have beentried, including the use of corticosteroids and other immunosuppressants,anticoagulants and antithrombolytics, and plasmapheresis andplasma exchange. The choice is usually made empirically or indesperation, and until the underlying pathobiology of MPGN IIis understood, effective and disease-specific therapies willnot exist.
Corticosteroids and Other Immunosuppressants
In children with MPGN types I through III, long-term controlledstudies of prednisone therapy have suggested a possible benefitas measured by a decrease in proteinuria and prolonged renalsurvival (25,72). However, in a randomized, placebo-controlledstudy, despite evidence of benefit in all patients with MPGNI through III when pooled together, children with MPGN II hadno better response to prednisone than to lactose, with treatmentfailure defined as a creatinine >350 mmol/L (4 mg/dl) in55.6% (five of nine) and 60% (three of five) of patients, respectively(73). Available data on steroid therapy in adults with MPGNII suggest a similar lack of efficacy (74).
When evaluated in small numbers of patients, the calcineurininhibitors also do not improve renal survival in MPGN II. Invitro studies with cyclosporin and tacrolimus have shown thatat therapeutic concentrations, neither drug suppresses C3 transcription(75). Given the evidence that uncontrolled activation of theAP of the complement cascade is the basis of MPGN II, it isnot surprising that these drugs are clinically ineffective immunomodulatorytreatment modalities.
There are no published data on the use of mycophenolate mofetilin MPGN II. Mycophenolate mofetil selectively blocks inosine5'-monophosphate dehydrogenase, an enzyme involved in the denovo synthesis of guanine nucleotides, and thus inhibits differentiation,maturation, and allostimulatory function of B and T lymphocytes.The use of rituximab, a chimeric IgG1 mAb that specificallytargets the CD20 surface antigen expressed on B lymphocytes,has not been studied in MPGN II.
A possibly noteworthy immunosuppressant is triptolide, becauseit has been shown to decrease renal complement synthesis attherapeutic concentrations (76). Triptolide is an extract ofTripterygium wilfordii hook f (Twhf), a woody vine-like shrubof Southern China and Taiwan commonly called the "thunder godvine." Although its place in traditional Chinese medicine datesback 2000 yr, only after Twhf was reported effective in patientswith leprosy and rheumatoid arthritis was its possible valuerecognized by Western physicians. Studies with triptolide areongoing, although use probably will be limited by its narrowtherapeutic window, which includes severe side effects in approximatelyone half of treated patients (77).
Anticoagulants and Antithrombolytics
One of the most conspicuous features of MPGN II is the increasein extracellular matrix and mesangial cell proliferation, makingheparin and heparin-derived GAG potentially interesting therapeutictreatment modalities. Heparin and heparin-derived GAG suppressextracellular matrix turnover, decrease proliferation of mesangialcells, reestablish the negative charge of the GBM and podocytes,and inhibit complement activation (78–81).
Heparin is a large molecule composed of a protein to which GAGside chains of variable composition and number are attached.This heterogeneity makes it difficult to compare different isolatesof heparin. There is considerable variation between individuallots in terms of biologic activity and exact chemical content,a heterogeneity that is compounded further in low molecularweight heparins by chemical modifications to alter anticoagulantproperties (79).
In a clinical trial using daily subcutaneous injections of heparinfor >1 yr, Cade et al. (81) reported improved creatinineclearance in nine of 10 patients with chronic proliferativeglomerulonephritis. Eight patients had pre- and posttreatmentrenal biopsies that showed a regression of glomerular hypercellularity.One patient in the treatment group died, as did four of eightpatients in a control group that received no therapy. No studieshave specifically investigated the efficacy of heparin or heparinoidsin patients with MPGN II, although in vivo and animal studiessuggest that these drugs may have a role in the treatment ofthis disease (78,79).
Plasmapheresis and Plasma Exchange
Removal of C3NeF from the serum through plasmapheresis has beenattempted in a few patients. In one study, one of three adultswith MPGN II experienced improvement in serum creatinine duringplasmapheresis (82). Another study reported success using plasmapheresisto treat a 5-yr-old boy with recurrent MPGN II after transplantation.Twelve phereses were performed over 24 d, and the patient continuedto have improved renal function 1 yr later (83). In anotherreport, a 15-yr-old girl with rapidly progressive recurrentMPGN II in her allograft underwent 73 phereses over 63 wk, stabilizingher creatinine and improving her creatinine clearance. Serialbiopsies during this time demonstrated persistent MPGN II withoutdevelopment of tubular atrophy. During the course of therapy,serum C3NeF activity decreased and C3NeF activity was detectedin the removed plasma. Because of the morbidity of repeatedphereses, treatment was discontinued and graft failure ensued(84).
Plasma exchange is an effective therapy in patients with MPGNII secondary to protein-inactivating mutations of fH (PeterF. Zipfel and Christoph Licht, Hans Knoell Institute, personalcommunication, December 2004). This therapy replaces deficientfH with normal fH, correcting the complement defect. Similarresults were seen in the fH-deficient pig. Untreated fH–/–pigs die by 7 wk of age but develop normally with plasma replacementtherapy (36). Most fascinating is the elegant study by Pickeringet al. (53) in which the MPGN II phenotype in the fH–/–mouse mutant was corrected in the fH–/–; fB–/–double homozygote knockout mouse. Although fH is absent in thismouse, the absence of fB prevents the formation of C3bBb, obviatingthe need for its inactivation by fH (Figure 6).
Replacement therapy with intravenous gamma globulin (IVIg) tointroduce potential blocking antibodies is theoretically possible,although the efficacy of this type of treatment has not beentested in patients with MPGN II. In patients with another autoimmunedisease, dermatomyositis, high-dose IVIg has been used to displacenascent C3b away from immune complexes by generating (C3b)2-IgGcomplexes (85). This displacement attenuates local complementactivation by scavenging nascent C3b. Although (C3b)2-IgG complexesare increased and these complexes are extremely potent activatorsof complement, constant region domains of IgG exert an anti-inflammatoryeffect through their capacity to bind and neutralize the anaphylatoxinsC3a and C5a (86). The net effect is that in patients with dermatomyositis,IVIg attenuates complement amplification to the extent thatit even compensates for the extra amounts of C3b that are generated(87).
Renal Allografts
Dense deposits recur in virtually all renal allografts, andalthough progression to ESRD is not inevitable, half of allograftsultimately fail (88–91). Studies in the fH-deficient pighave shown that within 24 h of renal allograft placement, recurrenceof glomerular complement deposits is demonstrable, presagingthe electron microscopic appearance of the dense deposits (36).It is pertinent to note that nephrectomized fH-deficient pigsremain hypocomplementemic, suggesting that the transplantedkidneys do not induce a consumptive hypocomplementemia (92).Unfortunately, long-term studies in fH-deficient pigs that receiveda transplant were never completed, so although dense depositsrecurred in the transplants, long-term outcome was never established(Tom-Eirik Mollnes, Institute of Immunology, University of Oslo,personal communication, December 2004). Whether modifying protocolsto include B cell suppression with drugs such as rituximab canincrease transplant survival rates in patients with MPGN IIis not known. Complement-specific suppression has not yet beentested.
Nonspecific Therapeutic Measures
Despite the lack of proven specific therapies for MPGN II, nonspecifictherapies have been shown to be effective in other chronic glomerulardiseases and should be initiated. Angiotensin-converting enzymeinhibitors and angiotensin II type-1 receptor blockers decreaseproteinuria in many glomerular diseases and slow progressionto renal failure (93,94). Lipid-lowering agents, in particularhydroxymethylglutaryl CoA reductase inhibitors, may also delayprogression of renal disease as well as correct endothelialcell dysfunction and alter long-term atherosclerotic risks (95,96).The judicious use of these agents, along with optimal BP control,may be of benefit in patients with MPGN II.
Available data on MPGN II support the following conclusions:
MPGN II is a rare disease that is diagnosed primarily in childrenbetween 5 and 15 yr of age. The disease is equally representedamong genders. Within 10 yr of diagnosis, ESRD develops in approximately50% of these children. In contrast to other forms of MPGN, MPGNII is not characterized by immune complex localization in glomeruli.
Diagnosis requires renal biopsy, which by electron microscopyshows osmophilic dense deposits in the GBM; C3 but not IgG isdemonstrable by immunofluorescence staining. Features of partiallipodystrophy and the development of ocular drusen can accompanyMPGN II. Drusen may lead to decreased visual acuity in approximately10% of patients with MPGN II. In view of the fundus similaritiesbetween individuals with MPGN II and age-related macular degeneration,it is conceivable that these disorders may share a common orrelated cause.
The pathophysiologic basis for MPGN II seemsto be the uncontrolledsystemic activation of the AP of thecomplement cascade. Thereare different triggers that resultin complement system dysfunction,including mutations in fH,antibodies directed against fH, andan autoantibody directedagainst C3bBb called C3NeF that ispresent in most people withMPGN II.
All C3NeF are not identical. It is possible thatC3NeF is normallypresent in many healthy people. The triggersthat lead to increasedand pathologic levels of C3NeF are notknown.
Most treatments for MPGN II are ineffective. Treatmentsto removeor suppress C3NeF activity include plasmapheresis,IVIg, andB cell suppression. The first has met with limitedsuccess;there is little experience with IVIg and B cell suppression.T cell suppressants are not effective. Consistent with thisobservation is the recurrence of disease in allografts withthe long-term outcome being graft failure in up to half of transplants.In patients with fH mutations, however, plasma exchange cancontrol complement activation and prevent ESRD. Although onlya few patients will have fH mutations, genetic screening offH should be completed on all patients with MPGN II.
Whetherlocal control of the complement cascade in the kidneycan preventESRD in the face of ongoing systemic activationof the AP ofcomplement is not known. If so, then it may bepossible to targettherapy to the kidney. One example mightbe the use of heparinoidsto protect the GBM from complementactivation. Another examplewould be the development of therapiesspecifically directedat controlling the AP of the complementsystem. Studies thatfocus on these modalities would seem tobe among the best avenuesto pursue to develop an effectivetreatment for MPGN II.
Acknowledgments
The MPGN II Focus Group was supported by a grant from the NationalInstitute of Diabetes and Digestive and Kidney Diseases (R13DK071183) and the Milagros Research Fund, in conjunction withKIDNEEDS and Franklin W. Olin College of Engineering.
We are particularly grateful to Dr. Richard K. Miller, Presidentof Franklin W. Olin College of Engineering, for guidance andsupport. Clara McAvoy and Giuliana Silvestri kindly providedthe fundus photo of MPGN II.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Top
Abstract
Introduction
light chain dimer was identified that bound to the SCR3 of fH and the anionic GBM, causing vigorous AP activation and C3 overconsumption (59). 
