Membranoproliferative Glomerulonephritis:Pathogenetic Heterogeneity and Proposal for a New Classification

Sanjeev Sethi, MD, PhD,* and Fernando C. Fervenza, MD, PhD†

Summary: Membranoproliferative glomerulonephritis (MPGN) is a pattern of injury that results from subendothe-lial and mesangial deposition of Igs caused by persistent antigenemia and/or circulating immune complexes. Thecommon causes of Ig-mediated MPGN include chronic infections, autoimmune diseases, and monoclonal gam-mopathy/dysproteinemias. On the other hand, MPGN also can result from subendothelial and mesangial depo-sition of complement owing to dysregulation of the alternative pathway (AP) of complement. Complement-mediated MPGN includes dense deposit disease and proliferative glomerulonephritis with C3 deposits.Dysregulation of the AP of complement can result from genetic mutations or development of autoantibodies tocomplement regulating proteins with ensuing dense deposit disease or glomerulonephritis with C3 deposits. Wepropose a new histologic classification of MPGN and classify MPGN into 2 major groups: Ig-mediated andcomplement-mediated. MPGN that is Ig-mediated should lead to work-up for infections, autoimmune diseases,and monoclonal gammopathy. On the other hand, complement-mediated MPGN should lead to work-up of the APof complement. Initial AP screening tests should include serum membrane attack complex levels, an AP functionalassay, and a hemolytic assay, followed by tests for mutations and autoantibodies to complement-regulatingproteins.Semin Nephrol 31:341-348 © 2011 Published by Elsevier Inc.Keywords: Membranoproliferative glomerulonephritis, MPGN, MGUS, monoclonal gammopathy, alternative path-way of complement, C3 glomerulopathy, C3-GN

ctam(

cpm

Membranoproliferative glomerulonephritis (MPGN)is a pattern of glomerular injury often associ-ated with subendothelial and/or mesangial de-

position (or in situ formation) of pathogenic immunecomplexes. Subendothelial and mesangial deposition ofimmune complexes can be the consequence of persistentantigenemia and circulating immune complexes. Thesecomplexes typically trigger activation of complementand a phase of acute injury in the glomerular capillariesand mesangium. Hence, the prominent finding of C3 onimmunofluorescence studies and low serum complementtiters. The immune complexes and activated complementfragments (C3a and C5a) in turn attract leukocytes duringthe active phase of the process and therefore the renalbiopsy often shows a proliferative/exudative picture withensuing endothelial and glomerular capillary wall injury.The acute injury phase is followed by a reparative phasein which the following changes occur as the mem-branoproliferative pattern of injury emerges: (1) endothe-lial cells and mesangial cells generate basement mem-brane–like material along with entrapment of immune

*Department of Laboratory Medicine and Pathology, Mayo Clinic,Rochester, Minnesota.

†Department of Internal Medicine, Division of Nephrology and Hy-pertension, Mayo Clinic, Rochester, Minnesota.

Supported in part by National Institutes of Health grant DK074409and the Fulk Family Foundation Award (Mayo Clinic) (S.S.).

Address reprint requests to Sanjeev Sethi, MD, PhD, Department ofLaboratory Medicine and Pathology, Mayo Clinic, 200 1st St SW,Rochester, MN 55905. E-mail: sethi.sanjeev@mayo.edu

0270-9295/ - see front matter© 2011 Published by Elsevier Inc.

doi:10.1016/j.semnephrol.2011.06.005

Seminars in Nephrology, Vol 31, No 4, July 2011, pp 341-348

omplexes and cellular elements to form double con-ours, and (2) mesangial expansion occurs as a result ofn increase in mesangial cellularity and infiltratingononuclear cells and an increase in mesangial matrix

Fig. 1).1,2 This pattern of glomerular injury often isreferred to as MPGN type I. Similar findings have beenobserved in monoclonal immunoglobulin deposition dis-eases (see later).

Alternatively, a MPGN pattern of injury, by lightmicroscopy, although less common than immune com-plex–mediated MPGN, also can appear as a result ofdysregulation of the alternative pathway (AP) of comple-ment cascade and secondary persistent complement acti-vation.3,4 This form of MPGN is not caused by immuneomplex deposition but is caused by deposition of com-lement products along the capillary walls and in theesangium.5 The prototypical example of this form of

MPGN is dense deposit disease (DDD) (also referred toas MPGN type II).4 DDD is often, but not exclusively,characterized by an MPGN pattern of injury, C3 depositson immunofluorescence (IF) microscopy, and the char-acteristic sausage-shaped, wavy, densely osmiophilic de-posits by electron microscopy along the glomerular base-ment membranes (GBM) and mesangium from which thedisease receives its name.3,4,6 However, some cases ofMPGN also show extensive C3 deposition with no sig-nificant Ig along the capillary walls and mesangium, butelectron microscopy (EM) fails to show the typical sau-sage-shaped intramembranous and mesangial deposits ofDDD. Instead, the deposits are very similar to those seenwith immune-complex–mediated MPGN. The terms glo-

merulonephritis with isolated C3 deposits (C3-GN) and

341

aiM

M

Melocgagl

342 S. Sethi and F.C. Fervenza

C3 glomerulopathy (C3G) have been used for this re-cently described entity.7-9 Finally, a pattern resemblingMPGN, but without Ig deposition, can be seen withchronic thrombotic microangiopathies.

Based on etiology, MPGN typically has been classi-fied as primary/idiopathic or secondary. Primary/idio-pathic MPGN includes immune-complex–mediated glo-merulonephritis MPGN types I and III and has been thesubject of recent reviews,10 whereas MPGN type II rep-resents DDD. Secondary MPGN is caused most com-monly by immune complex deposition in the mesangiumand along the capillary walls as a result of infections,autoimmune diseases, and monoclonal gammopathy.11-18

Herein, we review the pathogenesis of MPGN result-ing from various causes. In particular, we focus onMPGN resulting from monoclonal gammopathy andMPGN owing to dysfunction of the AP of complement.We also propose a simple (re)classification of MPGNbased on histopathology that focuses on the underlyingetiopathogenesis of the MPGN.

MPGN CAUSED BY IMMUNE COMPLEX DEPOSITION

MPGN and Infections

Chronic viral infections such as hepatitis C and hepa-titis B, with or without circulating cryoglobulins, arean important and common cause of MPGN. MPGNcaused by hepatitis has been the subject of excellentrecent reviews.1,2,12,19 In addition to viral infections,chronic bacterial and fungal infections causing endo-carditis, shunt nephritis, visceral abscesses, and soforth, all can result in MPGN. Bacteria associated withMPGN include Staphylococcus, Mycobacterium tuber-culosis, Streptococci, Propionibacterium acnes, Myco-plasma pneumoniae, Brucella, Coxiella burnetii, No-cardia, and meningococcus.13-15,20-30

MPGN and Autoimmune Diseases

Autoimmune diseases such as systemic lupus erythema-

Figure 1. Progression of disease. Histology of acute injury shows achronic, the MPGN pattern emerges.

tosus and occasionally Sjögren syndrome and rheumatoid

rthritis also are associated with persistent circulatingmmune complexes and the consequent development of

PGN.16,31,32 Renal biopsy features suggestive of auto-immune disease include a full-house pattern of immuno-globulin staining (IgG, IgA, and IgM) along with C3 andC1q deposits, tubular and vascular deposits, and tubularreticular inclusions in endothelial cells. Proliferative glo-merulonephritis including MPGN owing to systemic lu-pus erythematosus has been the subject of excellent re-cent reviews,17,33 and will not be discussed further here.

PGN andMonoclonal Gammopathy

onoclonal gammopathy is characterized by the prolif-ration of a single clone of immunoglobulin-producingymphocytes or plasma cells resulting in the circulationf monoclonal Igs. Dysproteinemia and plasma cell dys-rasia are other alternative terms used for monoclonalammopathy. The clinical spectrum of diseases associ-ted with monoclonal gammopathy includes monoclonalammopathy of undetermined significance (MGUS),ymphoproliferative disorders, and multiple myeloma.34

The majority of kidney diseases in monoclonal gam-mopathy are secondary to deposition of light chains(kappa or lambda) and not heavy chains or intact Igs.35

The spectrum of renal lesions associated with monoclo-nal gammopathy is extensive and depends on the physio-chemical properties of the immunoglobulin produced.36

These include myeloma kidney (myeloma cast nephrop-athy), AL amyloidosis, and light chain deposition dis-ease.37,38 Light-chain, heavy-chain, or monoclonal Ig de-position in the mesangium and along the GBM andtubular basement membranes also results in a MPGNpattern of injury with punctate granular deposits alongthe GBM and tubular basement membrane on electronmicroscopy (light chain, heavy chain, monoclonal Igdeposition disease). On the other hand, MPGN withimmune-type deposits from glomerular accumulation ofmonoclonal Igs owing to an underlying monoclonal gam-

e proliferative GN, and as the lesion progresses and becomes more

diffus

mopathy is less well recognized. In a recent study, we

Mltaii

gtlcobtas

ase

MPGN: an update 343

analyzed renal biopsies of Mayo Clinic patients diag-nosed with the light microscopic pattern of MPGN (afterexcluding all cases of infections and autoimmune dis-eases) over a 6-year period.18 Results were correlatedwith serum and urine electrophoretic studies and bonemarrow biopsies to clarify the relationship betweenMPGN and monoclonal gammopathy. Our study showedthat 41% of MPGN patients had serum and/or urineelectrophoresis studies positive for monoclonal gam-mopathy. Serum immunofixation electrophoresis (SIFE)was the most sensitive method for diagnosing monoclo-nal gammopathy, although in a few cases in the absenceof positive electrophoresis studies, an abnormal �/� freelight chain ratio was an early marker of an underlyingmonoclonal gammopathy. Renal biopsy showed a MPGNpattern of injury; IF microscopy using monoclonal pro-tein–specific reagents often was instrumental in diagnos-ing the underlying gammopathy, and EM showed double-contour formation with subendothelial deposits, cellulardebris, and new basement membrane formation. Figure 2shows renal biopsy findings in a representative case ofMPGN owing to monoclonal Ig deposits. Light micros-copy shows a MPGN pattern of injury, whereas IF mi-croscopy studies show staining for IgG and � light chains(and negative � light chains), and EM shows the suben-dothelial deposits and double-contour formation.

Based on the bone marrow biopsy, MGUS was themost common entity associated with MPGN. Other lesscommon causes of MPGN included multiple myeloma,low-grade B-cell lymphoma, and chronic lymphocyticleukemia (Fig. 3).39-41 Interestingly, cryoglobulins werenoted in only a very small minority of the patients withmonoclonal gammopathy. Another important finding ofthis study was the association of MPGN with MGUS.More than 50% of patients with MPGN and monoclonal

Figure 2. Representative case of MPGN secondary to monoclonalpattern of injury (magnification, �40). (B and D) Intense capillary wa�40). (C) Negative staining for � light chains (magnification, �40). (E(black arrows), and double-contour formation (white arrows).

gammopathy had an underlying MGUS. The diagnosis of

GUS requires a serum monoclonal paraprotein band ofess than 30 g/L, a bone marrow biopsy that shows lesshan 10% plasma cells, absence of lytic lesions, anemiand hypercalcemia, and absence of end-organ damage. Its the most common plasma cell disorder recognized ands a potential precursor for multiple myeloma.39,40,42,43 In

light of these findings, we believe that in patients withMPGN, the monoclonal gammopathy should not becalled of undetermined significance and should be calledmonoclonal gammopathy–related MPGN or monoclonalammopathy–associated MPGN. It should be pointed outhat MPGN often may be the first sign of the underlyingymphoplasmacytic disorder. An interesting and unusualomplication of MGUS may be the development of DDDr C3-GN, when the monoclonal Ig acts as an autoanti-ody to factor H (or other complement-regulating pro-eins) that on a permissive genetic background (the H402llele of factor H) lead to dysregulation of the AP withubsequent MPGN (see next section).42

Serum protein electrophoresis is a reasonably sensitivend rapid screening method to detect the M protein buthould always be followed by SIFE to confirm the pres-nce or absence of M protein and determine the specific

opathy. (A) Periodic acid–Schiff–stained section showing a MPGNmesangial staining for (B) IgG and (D) � light chains (magnification,) EM showing mesangial, subendothelial, and subepithelial deposits

gammll andand F

Figure 3. Summary of plasma cell and lymphoproliferative disordersassociated with MPGN.

dmir

hArst

344 S. Sethi and F.C. Fervenza

type of monoclonal Ig. SIFE also will detect smallamounts of M protein that easily can be missed by serumprotein electrophoresis. If the suspicion for monoclonalgammopathy is high, a �/� free light chain assay shouldbe performed if conventional electrophoresis studies arenegative. If positive, a bone marrow biopsy includingimmunophenotyping studies and flow cytometry studiesthen are warranted to determine whether the monoclonalgammopathy is owing to MGUS, or an underlyingplasma cell myeloma or lymphoproliferative disorder.

Recognition of monoclonal gammopathy–associatedMPGN is particularly important in the renal transplantsetting. We recently assessed renal allograft protocolbiopsies in MPGN patients to determine the incidenceand risk factors for recurrent disease. Patients with mono-clonal gammopathy have a particularly high incidence ofMPGN recurrence (67%) as compared with patientswithout monoclonal proteins (30%). Recent data fromour group also have shown that kidney transplantation inpatients with end-stage renal disease secondary to lightchain deposition disease or a monoclonal gammopathywith fibrillary deposits (also known as fibrillary andimmunotactoid glomerulopathy), both of which can beassociated with a MPGN pattern of injury, are associatedwith a high recurrence rate, with the transplant biopsyalso commonly showing a MPGN pattern of injury.43-45

MPGN CAUSED BYDYSREGULATION OF THE AP OF COMPLEMENT

C3G: DDD and C3-GN

Activation of the AP complement cascade occurs in asequential manner that can be divided into four mainsteps: initiation of complement activation, C3 convertaseactivation and amplification, C5 convertase activation,and terminal pathway activity with assembly of the ter-minal complement complex or membrane attack complex(MAC). Once activated, the AP generates effector com-pounds that are delivered to all surfaces indiscriminately,mandating control over progression of the cascade andthe action of these molecules. Multiple complement reg-ulators and inhibitors operate at every level to preventself-mediated damage.46-48 For example, proteins thatregulate C3 convertase (C3bBb) assembly, activity, andhalf-life include factor H, factor I, factor B, decay accel-erating factor, factor H–related proteins,49 membrane co-factor protein (CD46), and complement receptor 1. Mu-tations in, or antibodies against, these proteins thereforecan alter AP control and lead to the development ofMPGN. Genetic background also is a risk factor fordevelopment of disease. Best studied are the Tyr402Hisallele variants of factor H. His402 is over-represented inthe DDD patients as compared with Tyr402, and func-tional studies have shown that the former provides poorerfactor H–mediated regulation of the C3 convertase on

cell surfaces.5

Dysregulation of the AP can lead to complement-ebris–induced renal changes in the mesangium and glo-erular capillary walls that produce an MPGN pattern of

njury. DDD is the prototypical example of this type ofenal disease.3,4,6 It is characterized by an MPGN pattern

on light microscopy; C3 deposition in the mesangiumand along capillary walls on IF microscopy; and osmio-philic sausage-shaped, wavy, dense deposits along theGBM and in the mesangium on EM.7 The absence ofsignificant Igs by IF and the location and character of thedense EM deposits distinguish DDD from immune com-plex–mediated MPGN.

On the other hand, some cases of MPGN, however,show a pathology that is intermediate between immune-complex–mediated MPGN and DDD. In these cases ofMPGN, C3 deposition is present although there are nosignificant Ig deposits in the mesangium or along thecapillary walls. However, the EM studies do not showsausage-shaped, wavy, dense deposits. Instead, subendo-thelial (occasionally subepithelial) and mesangial depos-its are seen that resemble immune-complex MPGN. Fig-ure 4 shows renal biopsy findings in a representative caseof MPGN owing to C3 deposition. Light microscopyshows a MPGN pattern of injury, whereas IF studiesshow staining for C3 (with no significant Ig or �/� lightchains), and EM shows subendothelial, subepithelial, andmesangial electron dense deposits along with double-contour formation.

Studies have shown that these cases of MPGN with C3deposition, similar to DDD, also result from dysfunctionof AP caused by mutations or antibodies to the comple-ment-regulating proteins.7-9,50 Furthermore, review ofistology of these cases suggests that dysregulation of theP produces a spectrum of morphologic patterns that

ange from MPGN to mesangial proliferative GN or evenclerosing GN. Regarding terminology for this entity, theerms C3-GN and C3G have been proposed.5 We use the

term MPGN with C3 deposits in our renal biopsy practiceto indicate a proliferative GN associated with AP dys-function, but agree that C3-GN also is appropriate.50

Because both C3-GN and DDD are characterized by C3deposition in the absence of Ig deposition, we proposethat the term C3G be used to describe both DDD andC3-GN. On light and IF microscopy, DDD and C3-GNmay be difficult to distinguish. However, on EM DDDshows the typical sausage-shaped intramembranousdense deposits, whereas in C3-GN the deposits are mes-angial and subendothelial with few subepithelial depos-its. Tubular deposits are not typically noted in C3-GN,although they are present in DDD.

Laser microdissection and mass spectrometry data ofglomeruli from DDD and C3-GN are consistent with APactivation and show that the proteomic profile of C3-GNcases is similar to that of DDD. Complement proteins ofthe AP and terminal complement complex (TCC), as wellas complement-regulating proteins such as vitronectin,

clusterin, and factor H–related proteins, were found in

hposMlpMaA

cbegpith(

mesows)

MPGN: an update 345

the glomeruli of the C3-GN cases we studied. Proteins ofthe classic pathway such as C1 and C4 were not presentin any abundance in DDD or C3-GN. The similarity inproteomic profiles between C3-GN and DDD is consis-tent with a common pathogenesis for these diseases.49

Given the complexity of the AP cascade and thesimilarity between DDD and C3-GN, the observed EMdifferences may reflect differing degrees or sites of AP/serum MAC dysregulation. Alternatively, the response ofthe kidneys to complement damage also may affect theobserved pathology. That these diseases are part of acontinuum is supported by cases of MPGN with exten-sive C3 deposits that show features intermediate betweenDDD and C3-GN, with some capillary loops showingsausage-shaped intramembranous deposits whereas otherloops show immune-type subendothelial and subepithe-lial deposits.

The differential diagnosis of C3-GN includes postinfec-tious glomerulonephritis (owing to the presence of subepi-thelial humps) and autoimmune disease (owing to subepi-

Figure 4. Representative case of MPGN secondary to C3 depositipattern of injury (magnification, �40). (B) Intense capillary wall andmesangial, subendothelial, and subepithelial deposits (thin white arr

thelial, subendothelial, and mesangial deposits). The main l

istologic differentiating feature between C3-GN and aostinfectious or autoimmune proliferative GN is the lackf significant Igs on IF studies in the former. In addition,erum levels of C3 and C4 are low in Ig-mediatedPGN, whereas C4 levels are usually normal and C3

evels are usually low in C3G. This is because the classicathway of complement is activated in Ig-mediatedPGN, resulting in consumption of both C3 and C4,

lthough only C3 is consumed during activation of theP of complement.As indicated earlier, a MPGN pattern of injury also

an result from injury to the endothelial cells in throm-otic microangiopathies. In acute-phase mesangiolysis,ndothelial swelling and fibrin thrombi are present in thelomerular capillaries. As the reparative and chronichase sets in, mesangial expansion and glomerular cap-llary wall remodeling with double-contour formationakes place, resulting in a MPGN pattern. Thus, theealing phase of thrombotic thrombocytopenic purpuraTTP)/hemolytic uremic syndrome (HUS), antiphospho-

3-GN). (A) Periodic acid–Schiff–stained section showing a MPGNangial staining for C3 (magnification, �40). (C and D) EM showingand double-contour formation (thick arrows).

on (C

ipid antibody syndrome, drug-associated thrombotic mi-

346 S. Sethi and F.C. Fervenza

croangiopathy, nephropathy associated with bone marrowtransplantation, radiation nephritis, malignant hypertension,and so forth, can present with a MPGN pattern of injury. Inthese cases, Igs and complement typically are absent in theglomeruli, and EM does not show electron dense depositsalong the capillary walls.

The term transplant glomerulopathy is used to denotethe MPGN pattern of injury in the renal allograft. Trans-plant glomerulopathy is associated most often with thedevelopment of antibodies to human leukocyte antigenclass II molecules that are present on glomerular endo-thelial cells, resulting in antibody-mediated injury to theendothelial cells. In the acute phase neutrophils andmononuclear cells are noted in the glomerular capillaries(glomerulitis), which is followed by the reparative/

Figure 5. Proposed work-up of complement-mediated MPGN.APFA, alternative pathway functional assay; cFHRs, complementfactor H–related proteins; CR1, complement receptor 1; MCP, mem-brane cofactor protein; sMAC, serum MAC.

Figure 6. Proposed classification scheme for MPGN based on the presesignificant Igs and the presence of C3, the genetics and functional activi

chronic phase showing mesangial expansion and capil-lary wall remodeling, with development of double con-tours. This is similar to the Ig-mediated MPGN, and issupported by the positive staining for C4d (by product ofactivation of classic pathway of complement) along theglomerular capillaries.51-53

PROPOSAL FOR A NEW CLASSIFICATION OFMPGN

We propose that MPGN be classified into two majorgroups: Ig-mediated and complement-mediated (C3G). IfIgs are present on IF studies, the evaluation should in-clude a work-up for infections, autoimmune diseases, andmonoclonal gammopathies, including cryoglobulins. Itshould be kept in mind that Ig-mediated MPGN also isassociated with extensive C3 (and C4) deposition alongthe capillary walls via activation of the classic pathwayof complement. On the other hand, if the IF studies showpredominantly C3 (C3G) and are negative or show nosignificant staining for Igs, an in-depth study of the AP iswarranted. Ig-mediated MPGN is more likely to be pres-ent in adults whereas complement-mediated MPGN ismore likely to be present in children and young adults. Itis likely that C3G noted in children and young adults isdue to genetic mutations in complement-regulating pro-teins, whereas it is acquired in adults as a result ofdevelopment of autoantibodies to complement-regulatingproteins. Initial evaluation of AP should include serumMAC levels, an alternative pathway functional assay, andhemolytic complement assays. If the initial screening ispositive, it should be followed by genetic analysis formutations and enzyme-linked immunosorbent assays forthe presence of autoantibodies to complement-regulatingproteins (Figure 5). A simplified version of our interpre-tation of MPGN and proposal for the new classification isshown in Figure 6. The term idiopathic MPGN (or type

nce or absence of Igs and presence of C3 by IF. In the absence ofty of the AP should be assessed.

MPGN: an update 347

I or type III) should be used judiciously because it islikely that an underlying etiopathogenesis can be foundin almost every case of MPGN.

REFERENCES1. Smith KD, Alpers CE. Pathogenic mechanisms in membranopro-

liferative glomerulonephritis. Curr Opin Nephrol Hypertens.2005;14:396-403.

2. Rennke H. Secondary membranoproliferative glomerulonephritis.Kidney Int. 1995;47:643-56.

3. Appel GB, Cook HT, Hageman G, Jennette JC, et al. Mem-branoproliferative glomerulonephritis type ii (dense deposit dis-ease): an update. J Am Soc Nephrol. 2005;16:1392-403.

4. Smith RJH, Alexander J, Barlow PN, Botto M, et al. New ap-proaches to the treatment of dense deposit disease. J Am SocNephrol. 2007;18:2447-56.

5. Sethi S, Gamez JD, Vrana JA, Theis JD, et al. Glomeruli of densedeposit disease contain components of the alternative and termi-nal complement pathway. Kidney Int. 2009;75:952-60.

6. Nasr SH, Valeri AM, Appel GB, Sherwinter J, et al. Densedeposit disease: clinicopathologic study of 32 pediatric and adultpatients. Clin J Am Soc Nephrol. 2009;4:22-32.

7. Servais A, Frémeaux-Bacchi V, Lequintrec M, Salomon R, et al.Primary glomerulonephritis with isolated C3 deposits: a newentity which shares common genetic risk factors with haemolyticuraemic syndrome. J Med Genet. 2007;44:193-9.

8. Habbig S, Mihatsch MJ, Heinen S, Beck B, et al. C3 depositionglomerulopathy due to a functional factor H defect. Kidney Int.2009;75:1230-4.

9. Fakhouri F, Frémeaux-Bacchi V, Noël LH, Cook HT, et al. C3glomerulopathy: a new classification. Nat Rev Nephrol. 2010;6:494-9.

10. Hewins P, Smith RJH, Savage COS. Idiopathic membranoprolif-erative glomerulonephritis. In: Berl T, Himmelfarb J, Mitch WE,Murphy B, Wilcox CS, Salant DJ, Yu ASL, editors. Therapy inNephrology and Hypertension. A companion to Brenner & Rec-tor’s The Kidney, 3rd ed. Philadelphia:Elsevier Saunders; 2008.p. 249-56.

11. Yamabe H, Johnson RJ, Gretch DR, Fukushi K, et al. Hepatitis Cvirus infection and membranoproliferative glomerulonephritis inJapan. J Am Soc Nephrol. 1995;6:220-3.

12. Alpers CE, Smith KD. Cryoglobulinemia and renal disease. CurrOpin Nephrol Hypertens. 2008;17:243-9.

13. Hulton SA, Risdon RA, Dillon MJ. Mesangiocapillary glomeru-lonephritis associated with meningococcal meningitis, C3 ne-phritic factor and persistently low complement C3 and C5. PediatrNephrol. 1992;6:239-43.

14. Boseman P, Lewin M, Dillon J, Sethi S. Marfan syndrome,MPGN, and bacterial endocarditis. Am J Kidney Dis. 2008;51:697-701.

15. Vella J, Carmody M, Campbell E, Browne O, et al. Glomerulo-nephritis after ventriculo-atrial shunt. QJM. 1995;88:911-8.

16. Adam F, Torun D, Bolat F, Zumrutdal A, et al. Acute renal failuredue to mesangial proliferative glomerulonephritis in a pregnantwoman with primary Sjögren’s syndrome. Clin Rheumatol. 2006;25:75-9.

17. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, et al. Theclassification of glomerulonephritis in systemic lupus erythema-tosus revisited. Kidney Int. 2004;65:521-30.

18. Sethi S, Zand L, Leung N, Smith RJH, et al. Membranoprolifera-tive glomerulonephritis secondary to monoclonal gammopathy.Clin J Am Soc Nephrol. 2010;5:770-82.

19. Roccatello D, Fornasieri A, Giachino O, et al. Multicenter studyon hepatitis C virus related cryoglobulinemic glomerulonephritis.Am J Kidney Dis. 2007;49:69-82.

20. Ohara S, Kawasaki Y, Takano K, Isome M, et al. Glomerulone-

phritis associated with chronic infection from long-term centralvenous catheterization. Pediatr Nephrol. 2006;21:427-9.

21. Kai H, Shimizu Y, Hagiwara M, Yoh K, Hirayama K, YamagataK, et al. Post-MRSA infection glomerulonephritis with markedStaphylococcus aureus cell envelope antigen deposition in glom-eruli. J Nephrol. 2006;19:215-9.

22. Ades L, Akposso K, Costa de Beauregard MA, Haymann JP, et al.Bacterial endocarditis associated with crescentic glomerulone-phritis in a kidney transplant patient: first case report. Transplan-tation. 1998;66:653-4.

23. Pecchini F, Bufano G, Ghiringhelli P. Membranoproliferativeglomerulonephritis secondary to tuberculosis. Clin Nephrol.1997;47:63-4.

24. Bonarek H, Bonnet F, Delclaux C, Deminiere C, et al. Reversal ofc-ANCA positive mesangiocapillary glomerulonephritis after re-moval of an infected cysto-atrial shunt. Nephrol Dial Transplant.1999;14:1771-3.

25. del Carmen Laso Ma, Cadario Ma, Haymes L, Grimoldi I, et al.Mycoplasma pneumoniae detection with PCR in renal tissue of apatient with acute glomerulonephritis. Pediatr Nephrol. 2006;21:1483-6.

26. Altiparmak MR, Pamuk Gulum E, Pamuk Om N, Tabak F.Brucella glomerulonephritis: review of the literature and report onthe first patient with brucellosis and mesangiocapillary glomeru-lonephritis. Scand J Infect Dis. 2002;34:477-80.

27. Dathan JR, Heyworth MF. Glomerulonephritis associated withCoxiella burnetii endocarditis. Br Med J. 1975;1:376-7.

28. Jose M, Bannister K, Clarkson A, Whitehead F, et al. Mesangio-capillary glomerulonephritis in a patient with Nocardia pneumo-nia. Nephrol Dial Transplant. 1998;13:2628-9.

29. Elmaci I, Senday D, Silav G, Ekenel F, et al. Nocardial cerebralabscess associated with mycetoma, pneumonia and mem-branoproliferative glomerulonephritis. J Clin Microbiol. 2007;45:2072-4.

30. Haffner D, Schindera F, Aschoff A, Matthias S, et al. The clinicalspectrum of shunt nephritis. Nephrol Dial Transplant. 1997;12:1143-8.

31. Khan MA, Akhtar M, Taher SM. Membranoproliferative glomer-ulonephritis in a patient with primary Sjögren’s syndrome. Reportof a case with review of the literature. Am J Nephrol. 1988;8:235-9.

32. Korpela M, Mustonen J, Teppo AM, Helin H, et al. Mesangialglomerulonephritis as an extra-articular manifestation of rheuma-toid arthritis. Rheumatology. 1997;36:1189-95.

33. Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, et al. Theclassification of glomerulonephritis in systemic lupus erythema-tosus revisited. J Am Soc Nephrol. 2004;15:241-50.

34. Sanders P, Herrera G. Monoclonal immunoglobulin light chain-related renal diseases. Semin Nephrol. 1993;13:324-41.

35. Audard V, Georges B, Vanhille P, Toly C, et al. Renal lesionsassociated with IgM-secreting monoclonal proliferations: re-visiting the disease spectrum. Clin J Am Soc Nephrol. 2008;3:1339-49.

36. Leung N, Rajkumar SV. Renal manifestations of plasma celldisorders. Am J Kidney Dis. 2007;50:155-65.

37. Salant DJ, Sanchorawala V, D’Agati VD. A case of atypical lightchain deposition disease—diagnosis and treatment. Clin J AmSoc Nephrol. 2007;2:858-67.

38. Mutluay R, Aki SZ, Erten Y, Konca C, et al. Membranoprolif-erative glomerulonephritis and light-chain nephropathy in associ-ation with chronic lymphocytic leukemia. Clin Nephrol. 2008;70:527-31.

39. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, et al. Prev-alence of monoclonal gammopathy of undetermined significance.N Engl J Med. 2006;354:1362-9.

40. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, et al. Along-term study of prognosis in monoclonal gammopathy of

undetermined significance. N Engl J Med. 2002;346:564-9.

348 S. Sethi and F.C. Fervenza

41. Robert A. Kyle SVR. Monoclonal gammopathy of undeterminedsignificance. Br J Haematol. 2006;134:573-89.

42. Sethi S, Sukov W, Zhang Y, Fervenza F, et al. Dense depositdisease associated with monoclonal gammopathy of undeter-mined significance. Am J Kidney Dis. 2010;56:977-82.

43. Czarnecki PG, Lager DJ, Leung N, Dispenzieri A, et al. Long-term outcome of kidney transplantation in patients with fibrillaryglomerulonephritis or monoclonal gammopathy with fibrillarydeposits. Kidney Int. 2009;75:420-7.

44. Leung N, Lager DJ, Gertz MA, Wilson K, et al. Long-termoutcome of renal transplantation in light-chain deposition disease.Am J Kidney Dis. 2004;43:147-53.

45. Lorenz EC, Sethi S, Leung N, Dispenzieri A, et al. Recurrentmembranoproliferative glomerulonephritis after kidney transplan-tation. Kidney Int. 2010;77:721-8.

46. Zipfel PF, Skerka C. Complement regulators and inhibitory pro-teins. Nat Rev Immunol. 2009;9:729-40.

47. Abrera-Abeleda MA, Nishimura C, Smith JLH, Sethi S, et al.Variations in the complement regulatory genes factor H (CFH)

and factor H related 5 (CFHR5) are associated with mem-

branoproliferative glomerulonephritis type II (dense depositdisease). J Med Genet. 2006;43:582-9.

48. Skerka C, Lauer N, Weinberger AAWA, Keilhauer CN, et al. De-fective complement control of Factor H (Y402H) and FHL-1 inage-related macular degeneration. Mol Immunol. 2007;44:3398-406.

49. Gale DP, de Jorge EG, Cook HT, et al. Identification of amutation in complement factor H-related protein 5 in patients ofCypriot origin with glomerulonephritis. The Lancet. 2010;376:794-801.

50. Sethi S, Fervenza F, Zhang Y, Nasr S, et al. Proliferative glomer-ulonephritis secondary to dysfunction of the alternative pathway.Clin J Am Soc Nephrol. 2011;6:1009-17.

51. Cosio FG, Gloor JM, Sethi S, Stegall MD. Transplant glomeru-lopathy. Am J Transplant. 2008;8:492-6.

52. Gloor JM, Sethi S, Stegall MD, Park WD, et al. Transplantglomerulopathy: subclinical incidence and association with al-loantibody. Am J Transplant. 2007;7:2124-32.

53. Issa N, Cosio FG, Gloor JM, Sethi S, et al. Transplant glo-merulopathy: risk and prognosis related to anti-human leuko-cyte antigen class II antibody levels. Transplantation. 2008;

86:681-5.