Membranoproliferative Glomerulonephritis: Pathogenetic Heterogeneity and Proposal for a New Classication

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

Summary: Membranoproliferative glomerulonephritis (MPGN) is a pattern of injury that results from subendothelial and mesangial deposition of Igs caused by persistent antigenemia and/or circulating immune complexes. The common causes of Ig-mediated MPGN include chronic infections, autoimmune diseases, and monoclonal gammopathy/dysproteinemias. On the other hand, MPGN also can result from subendothelial and mesangial deposition of complement owing to dysregulation of the alternative pathway (AP) of complement. Complementmediated 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 to complement regulating proteins with ensuing dense deposit disease or glomerulonephritis with C3 deposits. We propose a new histologic classication of MPGN and classify MPGN into 2 major groups: Ig-mediated and complement-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 AP of complement. Initial AP screening tests should include serum membrane attack complex levels, an AP functional assay, and a hemolytic assay, followed by tests for mutations and autoantibodies to complement-regulating proteins. Semin Nephrol 31:341-348 2011 Published by Elsevier Inc. Keywords: Membranoproliferative glomerulonephritis, MPGN, MGUS, monoclonal gammopathy, alternative pathway of complement, C3 glomerulopathy, C3-GN

embranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular injury often associated with subendothelial and/or mesangial deposition (or in situ formation) of pathogenic immune complexes. Subendothelial and mesangial deposition of immune complexes can be the consequence of persistent antigenemia and circulating immune complexes. These complexes typically trigger activation of complement and a phase of acute injury in the glomerular capillaries and mesangium. Hence, the prominent nding of C3 on immunouorescence studies and low serum complement titers. The immune complexes and activated complement fragments (C3a and C5a) in turn attract leukocytes during the active phase of the process and therefore the renal biopsy often shows a proliferative/exudative picture with ensuing endothelial and glomerular capillary wall injury. The acute injury phase is followed by a reparative phase in which the following changes occur as the membranoproliferative pattern of injury emerges: (1) endothelial cells and mesangial cells generate basement membranelike material along with entrapment of immune
*Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota. Supported in part by National Institutes of Health grant DK074409 and the Fulk Family Foundation Award (Mayo Clinic) (S.S.). Address reprint requests to Sanjeev Sethi, MD, PhD, Department of Laboratory 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

complexes and cellular elements to form double contours, and (2) mesangial expansion occurs as a result of an increase in mesangial cellularity and inltrating mononuclear cells and an increase in mesangial matrix (Fig. 1).1,2 This pattern of glomerular injury often is referred to as MPGN type I. Similar ndings have been observed in monoclonal immunoglobulin deposition diseases (see later). Alternatively, a MPGN pattern of injury, by light microscopy, although less common than immune complexmediated MPGN, also can appear as a result of dysregulation of the alternative pathway (AP) of complement cascade and secondary persistent complement activation.3,4 This form of MPGN is not caused by immune complex deposition but is caused by deposition of complement products along the capillary walls and in the mesangium.5 The prototypical example of this form of MPGN is dense deposit disease (DDD) (also referred to as MPGN type II).4 DDD is often, but not exclusively, characterized by an MPGN pattern of injury, C3 deposits on immunouorescence (IF) microscopy, and the characteristic sausage-shaped, wavy, densely osmiophilic deposits by electron microscopy along the glomerular basement membranes (GBM) and mesangium from which the disease receives its name.3,4,6 However, some cases of MPGN also show extensive C3 deposition with no signicant Ig along the capillary walls and mesangium, but electron microscopy (EM) fails to show the typical sausage-shaped intramembranous and mesangial deposits of DDD. Instead, the deposits are very similar to those seen with immune-complexmediated MPGN. The terms glomerulonephritis with isolated C3 deposits (C3-GN) and
341

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

342

S. Sethi and F.C. Fervenza

Figure 1. Progression of disease. Histology of acute injury shows a diffuse proliferative GN, and as the lesion progresses and becomes more chronic, the MPGN pattern emerges.

C3 glomerulopathy (C3G) have been used for this recently described entity.7-9 Finally, a pattern resembling MPGN, but without Ig deposition, can be seen with chronic thrombotic microangiopathies. Based on etiology, MPGN typically has been classied as primary/idiopathic or secondary. Primary/idiopathic MPGN includes immune-complexmediated glomerulonephritis MPGN types I and III and has been the subject of recent reviews,10 whereas MPGN type II represents DDD. Secondary MPGN is caused most commonly by immune complex deposition in the mesangium and along the capillary walls as a result of infections, autoimmune diseases, and monoclonal gammopathy.11-18 Herein, we review the pathogenesis of MPGN resulting from various causes. In particular, we focus on MPGN resulting from monoclonal gammopathy and MPGN owing to dysfunction of the AP of complement. We also propose a simple (re)classication of MPGN based on histopathology that focuses on the underlying etiopathogenesis of the MPGN.

arthritis also are associated with persistent circulating immune complexes and the consequent development of MPGN.16,31,32 Renal biopsy features suggestive of autoimmune disease include a full-house pattern of immunoglobulin staining (IgG, IgA, and IgM) along with C3 and C1q deposits, tubular and vascular deposits, and tubular reticular inclusions in endothelial cells. Proliferative glomerulonephritis including MPGN owing to systemic lupus erythematosus has been the subject of excellent recent reviews,17,33 and will not be discussed further here. MPGN and Monoclonal Gammopathy Monoclonal gammopathy is characterized by the proliferation of a single clone of immunoglobulin-producing lymphocytes or plasma cells resulting in the circulation of monoclonal Igs. Dysproteinemia and plasma cell dyscrasia are other alternative terms used for monoclonal gammopathy. The clinical spectrum of diseases associated with monoclonal gammopathy includes monoclonal gammopathy of undetermined signicance (MGUS), lymphoproliferative disorders, and multiple myeloma.34 The majority of kidney diseases in monoclonal gammopathy 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 monoclonal gammopathy is extensive and depends on the physiochemical properties of the immunoglobulin produced.36 These include myeloma kidney (myeloma cast nephropathy), AL amyloidosis, and light chain deposition disease.37,38 Light-chain, heavy-chain, or monoclonal Ig deposition in the mesangium and along the GBM and tubular basement membranes also results in a MPGN pattern of injury with punctate granular deposits along the GBM and tubular basement membrane on electron microscopy (light chain, heavy chain, monoclonal Ig deposition disease). On the other hand, MPGN with immune-type deposits from glomerular accumulation of monoclonal Igs owing to an underlying monoclonal gammopathy is less well recognized. In a recent study, we

MPGN CAUSED BY IMMUNE COMPLEX DEPOSITION

MPGN and Infections Chronic viral infections such as hepatitis C and hepatitis B, with or without circulating cryoglobulins, are an important and common cause of MPGN. MPGN caused by hepatitis has been the subject of excellent recent reviews.1,2,12,19 In addition to viral infections, chronic bacterial and fungal infections causing endocarditis, shunt nephritis, visceral abscesses, and so forth, all can result in MPGN. Bacteria associated with MPGN include Staphylococcus, Mycobacterium tuberculosis, Streptococci, Propionibacterium acnes, Mycoplasma pneumoniae, Brucella, Coxiella burnetii, Nocardia, and meningococcus.13-15,20-30 MPGN and Autoimmune Diseases Autoimmune diseases such as systemic lupus erythematosus and occasionally Sjgren syndrome and rheumatoid

MPGN: an update

343

Figure 2. Representative case of MPGN secondary to monoclonal gammopathy. (A) Periodic acidSchiffstained section showing a MPGN pattern of injury (magnication, 40). (B and D) Intense capillary wall and mesangial staining for (B) IgG and (D) light chains (magnication, 40). (C) Negative staining for light chains (magnication, 40). (E and F) EM showing mesangial, subendothelial, and subepithelial deposits (black arrows), and double-contour formation (white arrows).

analyzed renal biopsies of Mayo Clinic patients diagnosed with the light microscopic pattern of MPGN (after excluding all cases of infections and autoimmune diseases) over a 6-year period.18 Results were correlated with serum and urine electrophoretic studies and bone marrow biopsies to clarify the relationship between MPGN and monoclonal gammopathy. Our study showed that 41% of MPGN patients had serum and/or urine electrophoresis studies positive for monoclonal gammopathy. Serum immunoxation electrophoresis (SIFE) was the most sensitive method for diagnosing monoclonal gammopathy, although in a few cases in the absence of positive electrophoresis studies, an abnormal / free light chain ratio was an early marker of an underlying monoclonal gammopathy. Renal biopsy showed a MPGN pattern of injury; IF microscopy using monoclonal proteinspecic reagents often was instrumental in diagnosing the underlying gammopathy, and EM showed doublecontour formation with subendothelial deposits, cellular debris, and new basement membrane formation. Figure 2 shows renal biopsy ndings in a representative case of MPGN owing to monoclonal Ig deposits. Light microscopy shows a MPGN pattern of injury, whereas IF microscopy studies show staining for IgG and light chains (and negative light chains), and EM shows the subendothelial deposits and double-contour formation. Based on the bone marrow biopsy, MGUS was the most common entity associated with MPGN. Other less common causes of MPGN included multiple myeloma, low-grade B-cell lymphoma, and chronic lymphocytic leukemia (Fig. 3).39-41 Interestingly, cryoglobulins were noted in only a very small minority of the patients with monoclonal gammopathy. Another important nding of this study was the association of MPGN with MGUS. More than 50% of patients with MPGN and monoclonal gammopathy had an underlying MGUS. The diagnosis of

MGUS requires a serum monoclonal paraprotein band of less than 30 g/L, a bone marrow biopsy that shows less than 10% plasma cells, absence of lytic lesions, anemia and hypercalcemia, and absence of end-organ damage. It is the most common plasma cell disorder recognized and is a potential precursor for multiple myeloma.39,40,42,43 In light of these ndings, we believe that in patients with MPGN, the monoclonal gammopathy should not be called of undetermined signicance and should be called monoclonal gammopathyrelated MPGN or monoclonal gammopathyassociated MPGN. It should be pointed out that MPGN often may be the rst sign of the underlying lymphoplasmacytic disorder. An interesting and unusual complication of MGUS may be the development of DDD or C3-GN, when the monoclonal Ig acts as an autoantibody to factor H (or other complement-regulating proteins) that on a permissive genetic background (the H402 allele of factor H) lead to dysregulation of the AP with subsequent MPGN (see next section).42 Serum protein electrophoresis is a reasonably sensitive and rapid screening method to detect the M protein but should always be followed by SIFE to conrm the presence or absence of M protein and determine the specic

Figure 3. Summary of plasma cell and lymphoproliferative disorders associated with MPGN.

344

S. Sethi and F.C. Fervenza

type of monoclonal Ig. SIFE also will detect small amounts of M protein that easily can be missed by serum protein electrophoresis. If the suspicion for monoclonal gammopathy is high, a / free light chain assay should be performed if conventional electrophoresis studies are negative. If positive, a bone marrow biopsy including immunophenotyping studies and ow cytometry studies then are warranted to determine whether the monoclonal gammopathy is owing to MGUS, or an underlying plasma cell myeloma or lymphoproliferative disorder. Recognition of monoclonal gammopathyassociated MPGN is particularly important in the renal transplant setting. We recently assessed renal allograft protocol biopsies in MPGN patients to determine the incidence and risk factors for recurrent disease. Patients with monoclonal gammopathy have a particularly high incidence of MPGN recurrence (67%) as compared with patients without monoclonal proteins (30%). Recent data from our group also have shown that kidney transplantation in patients with end-stage renal disease secondary to light chain deposition disease or a monoclonal gammopathy with brillary deposits (also known as brillary and immunotactoid glomerulopathy), both of which can be associated with a MPGN pattern of injury, are associated with a high recurrence rate, with the transplant biopsy also commonly showing a MPGN pattern of injury.43-45

MPGN CAUSED BY DYSREGULATION OF THE AP OF COMPLEMENT

C3G: DDD and C3-GN Activation of the AP complement cascade occurs in a sequential manner that can be divided into four main steps: initiation of complement activation, C3 convertase activation and amplication, C5 convertase activation, and terminal pathway activity with assembly of the terminal complement complex or membrane attack complex (MAC). Once activated, the AP generates effector compounds that are delivered to all surfaces indiscriminately, mandating control over progression of the cascade and the action of these molecules. Multiple complement regulators and inhibitors operate at every level to prevent self-mediated damage.46-48 For example, proteins that regulate C3 convertase (C3bBb) assembly, activity, and half-life include factor H, factor I, factor B, decay accelerating factor, factor Hrelated proteins,49 membrane cofactor protein (CD46), and complement receptor 1. Mutations in, or antibodies against, these proteins therefore can alter AP control and lead to the development of MPGN. Genetic background also is a risk factor for development of disease. Best studied are the Tyr402His allele variants of factor H. His402 is over-represented in the DDD patients as compared with Tyr402, and functional studies have shown that the former provides poorer factor Hmediated regulation of the C3 convertase on cell surfaces.5

Dysregulation of the AP can lead to complementdebrisinduced renal changes in the mesangium and glomerular capillary walls that produce an MPGN pattern of injury. DDD is the prototypical example of this type of renal disease.3,4,6 It is characterized by an MPGN pattern on light microscopy; C3 deposition in the mesangium and along capillary walls on IF microscopy; and osmiophilic sausage-shaped, wavy, dense deposits along the GBM and in the mesangium on EM.7 The absence of signicant Igs by IF and the location and character of the dense EM deposits distinguish DDD from immune complexmediated MPGN. On the other hand, some cases of MPGN, however, show a pathology that is intermediate between immunecomplexmediated MPGN and DDD. In these cases of MPGN, C3 deposition is present although there are no signicant Ig deposits in the mesangium or along the capillary walls. However, the EM studies do not show sausage-shaped, wavy, dense deposits. Instead, subendothelial (occasionally subepithelial) and mesangial deposits are seen that resemble immune-complex MPGN. Figure 4 shows renal biopsy ndings in a representative case of MPGN owing to C3 deposition. Light microscopy shows a MPGN pattern of injury, whereas IF studies show staining for C3 (with no signicant Ig or / light chains), and EM shows subendothelial, subepithelial, and mesangial electron dense deposits along with doublecontour formation. Studies have shown that these cases of MPGN with C3 deposition, similar to DDD, also result from dysfunction of AP caused by mutations or antibodies to the complement-regulating proteins.7-9,50 Furthermore, review of histology of these cases suggests that dysregulation of the AP produces a spectrum of morphologic patterns that range from MPGN to mesangial proliferative GN or even sclerosing GN. Regarding terminology for this entity, the terms C3-GN and C3G have been proposed.5 We use the term MPGN with C3 deposits in our renal biopsy practice to indicate a proliferative GN associated with AP dysfunction, but agree that C3-GN also is appropriate.50 Because both C3-GN and DDD are characterized by C3 deposition in the absence of Ig deposition, we propose that the term C3G be used to describe both DDD and C3-GN. On light and IF microscopy, DDD and C3-GN may be difcult to distinguish. However, on EM DDD shows the typical sausage-shaped intramembranous dense deposits, whereas in C3-GN the deposits are mesangial and subendothelial with few subepithelial deposits. Tubular deposits are not typically noted in C3-GN, although they are present in DDD. Laser microdissection and mass spectrometry data of glomeruli from DDD and C3-GN are consistent with AP activation and show that the proteomic prole of C3-GN cases is similar to that of DDD. Complement proteins of the AP and terminal complement complex (TCC), as well as complement-regulating proteins such as vitronectin, clusterin, and factor Hrelated proteins, were found in

MPGN: an update

345

Figure 4. Representative case of MPGN secondary to C3 deposition (C3-GN). (A) Periodic acidSchiffstained section showing a MPGN pattern of injury (magnication, 40). (B) Intense capillary wall and mesangial staining for C3 (magnication, 40). (C and D) EM showing mesangial, subendothelial, and subepithelial deposits (thin white arrows) and double-contour formation (thick arrows).

the glomeruli of the C3-GN cases we studied. Proteins of the classic pathway such as C1 and C4 were not present in any abundance in DDD or C3-GN. The similarity in proteomic proles between C3-GN and DDD is consistent with a common pathogenesis for these diseases.49 Given the complexity of the AP cascade and the similarity between DDD and C3-GN, the observed EM differences may reect differing degrees or sites of AP/ serum MAC dysregulation. Alternatively, the response of the kidneys to complement damage also may affect the observed pathology. That these diseases are part of a continuum is supported by cases of MPGN with extensive C3 deposits that show features intermediate between DDD and C3-GN, with some capillary loops showing sausage-shaped intramembranous deposits whereas other loops show immune-type subendothelial and subepithelial deposits. The differential diagnosis of C3-GN includes postinfectious glomerulonephritis (owing to the presence of subepithelial humps) and autoimmune disease (owing to subepithelial, subendothelial, and mesangial deposits). The main

histologic differentiating feature between C3-GN and a postinfectious or autoimmune proliferative GN is the lack of signicant Igs on IF studies in the former. In addition, serum levels of C3 and C4 are low in Ig-mediated MPGN, whereas C4 levels are usually normal and C3 levels are usually low in C3G. This is because the classic pathway of complement is activated in Ig-mediated MPGN, resulting in consumption of both C3 and C4, although only C3 is consumed during activation of the AP of complement. As indicated earlier, a MPGN pattern of injury also can result from injury to the endothelial cells in thrombotic microangiopathies. In acute-phase mesangiolysis, endothelial swelling and brin thrombi are present in the glomerular capillaries. As the reparative and chronic phase sets in, mesangial expansion and glomerular capillary wall remodeling with double-contour formation takes place, resulting in a MPGN pattern. Thus, the healing phase of thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS), antiphospholipid antibody syndrome, drug-associated thrombotic mi-

346

S. Sethi and F.C. Fervenza

chronic phase showing mesangial expansion and capillary wall remodeling, with development of double contours. This is similar to the Ig-mediated MPGN, and is supported by the positive staining for C4d (by product of activation of classic pathway of complement) along the glomerular capillaries.51-53

PROPOSAL FOR A NEW CLASSIFICATION OF MPGN

We propose that MPGN be classied into two major groups: Ig-mediated and complement-mediated (C3G). If Igs are present on IF studies, the evaluation should include a work-up for infections, autoimmune diseases, and monoclonal gammopathies, including cryoglobulins. It should be kept in mind that Ig-mediated MPGN also is associated with extensive C3 (and C4) deposition along the capillary walls via activation of the classic pathway of complement. On the other hand, if the IF studies show predominantly C3 (C3G) and are negative or show no signicant staining for Igs, an in-depth study of the AP is warranted. Ig-mediated MPGN is more likely to be present in adults whereas complement-mediated MPGN is more likely to be present in children and young adults. It is likely that C3G noted in children and young adults is due to genetic mutations in complement-regulating proteins, whereas it is acquired in adults as a result of development of autoantibodies to complement-regulating proteins. Initial evaluation of AP should include serum MAC levels, an alternative pathway functional assay, and hemolytic complement assays. If the initial screening is positive, it should be followed by genetic analysis for mutations and enzyme-linked immunosorbent assays for the presence of autoantibodies to complement-regulating proteins (Figure 5). A simplied version of our interpretation of MPGN and proposal for the new classication is shown in Figure 6. The term idiopathic MPGN (or type

Figure 5. Proposed work-up of complement-mediated MPGN. APFA, alternative pathway functional assay; cFHRs, complement factor Hrelated proteins; CR1, complement receptor 1; MCP, membrane cofactor protein; sMAC, serum MAC.

croangiopathy, nephropathy associated with bone marrow transplantation, radiation nephritis, malignant hypertension, and so forth, can present with a MPGN pattern of injury. In these cases, Igs and complement typically are absent in the glomeruli, and EM does not show electron dense deposits along the capillary walls. The term transplant glomerulopathy is used to denote the MPGN pattern of injury in the renal allograft. Transplant glomerulopathy is associated most often with the development of antibodies to human leukocyte antigen class II molecules that are present on glomerular endothelial cells, resulting in antibody-mediated injury to the endothelial cells. In the acute phase neutrophils and mononuclear cells are noted in the glomerular capillaries (glomerulitis), which is followed by the reparative/

Figure 6. Proposed classication scheme for MPGN based on the presence or absence of Igs and presence of C3 by IF. In the absence of signicant Igs and the presence of C3, the genetics and functional activity of the AP should be assessed.

MPGN: an update

347
phritis associated with chronic infection from long-term central venous catheterization. Pediatr Nephrol. 2006;21:427-9. Kai H, Shimizu Y, Hagiwara M, Yoh K, Hirayama K, Yamagata K, et al. Post-MRSA infection glomerulonephritis with marked Staphylococcus aureus cell envelope antigen deposition in glomeruli. J Nephrol. 2006;19:215-9. Ades L, Akposso K, Costa de Beauregard MA, Haymann JP, et al. Bacterial endocarditis associated with crescentic glomerulonephritis in a kidney transplant patient: rst case report. Transplantation. 1998;66:653-4. Pecchini F, Bufano G, Ghiringhelli P. Membranoproliferative glomerulonephritis secondary to tuberculosis. Clin Nephrol. 1997;47:63-4. Bonarek H, Bonnet F, Delclaux C, Deminiere C, et al. Reversal of c-ANCA positive mesangiocapillary glomerulonephritis after removal of an infected cysto-atrial shunt. Nephrol Dial Transplant. 1999;14:1771-3. del Carmen Laso Ma, Cadario Ma, Haymes L, Grimoldi I, et al. Mycoplasma pneumoniae detection with PCR in renal tissue of a patient with acute glomerulonephritis. Pediatr Nephrol. 2006;21: 1483-6. Altiparmak MR, Pamuk Gulum E, Pamuk Om N, Tabak F. Brucella glomerulonephritis: review of the literature and report on the rst patient with brucellosis and mesangiocapillary glomerulonephritis. Scand J Infect Dis. 2002;34:477-80. Dathan JR, Heyworth MF. Glomerulonephritis associated with Coxiella burnetii endocarditis. Br Med J. 1975;1:376-7. Jose M, Bannister K, Clarkson A, Whitehead F, et al. Mesangiocapillary glomerulonephritis in a patient with Nocardia pneumonia. Nephrol Dial Transplant. 1998;13:2628-9. Elmaci I, Senday D, Silav G, Ekenel F, et al. Nocardial cerebral abscess associated with mycetoma, pneumonia and membranoproliferative glomerulonephritis. J Clin Microbiol. 2007;45: 2072-4. Haffner D, Schindera F, Aschoff A, Matthias S, et al. The clinical spectrum of shunt nephritis. Nephrol Dial Transplant. 1997;12: 1143-8. Khan MA, Akhtar M, Taher SM. Membranoproliferative glomerulonephritis in a patient with primary Sjgrens syndrome. Report of a case with review of the literature. Am J Nephrol. 1988;8: 235-9. Korpela M, Mustonen J, Teppo AM, Helin H, et al. Mesangial glomerulonephritis as an extra-articular manifestation of rheumatoid arthritis. Rheumatology. 1997;36:1189-95. Weening JJ, DAgati VD, Schwartz MM, Seshan SV, et al. The classication of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15:241-50. Sanders P, Herrera G. Monoclonal immunoglobulin light chainrelated renal diseases. Semin Nephrol. 1993;13:324-41. Audard V, Georges B, Vanhille P, Toly C, et al. Renal lesions associated with IgM-secreting monoclonal proliferations: revisiting the disease spectrum. Clin J Am Soc Nephrol. 2008; 3:1339-49. Leung N, Rajkumar SV. Renal manifestations of plasma cell disorders. Am J Kidney Dis. 2007;50:155-65. Salant DJ, Sanchorawala V, DAgati VD. A case of atypical light chain deposition disease diagnosis and treatment. Clin J Am Soc Nephrol. 2007;2:858-67. Mutluay R, Aki SZ, Erten Y, Konca C, et al. Membranoproliferative glomerulonephritis and light-chain nephropathy in association with chronic lymphocytic leukemia. Clin Nephrol. 2008;70: 527-31. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, et al. Prevalence of monoclonal gammopathy of undetermined signicance. N Engl J Med. 2006;354:1362-9. Kyle RA, Therneau TM, Rajkumar SV, Offord JR, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined signicance. N Engl J Med. 2002;346:564-9.

I or type III) should be used judiciously because it is likely that an underlying etiopathogenesis can be found in almost every case of MPGN.

21.

REFERENCES
1. Smith KD, Alpers CE. Pathogenic mechanisms in membranoproliferative 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. Membranoproliferative glomerulonephritis type ii (dense deposit disease): an update. J Am Soc Nephrol. 2005;16:1392-403. 4. Smith RJH, Alexander J, Barlow PN, Botto M, et al. New approaches to the treatment of dense deposit disease. J Am Soc Nephrol. 2007;18:2447-56. 5. Sethi S, Gamez JD, Vrana JA, Theis JD, et al. Glomeruli of dense deposit disease contain components of the alternative and terminal complement pathway. Kidney Int. 2009;75:952-60. 6. Nasr SH, Valeri AM, Appel GB, Sherwinter J, et al. Dense deposit disease: clinicopathologic study of 32 pediatric and adult patients. Clin J Am Soc Nephrol. 2009;4:22-32. 7. Servais A, Frmeaux-Bacchi V, Lequintrec M, Salomon R, 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;44:193-9. 8. Habbig S, Mihatsch MJ, Heinen S, Beck B, et al. C3 deposition glomerulopathy due to a functional factor H defect. Kidney Int. 2009;75:1230-4. 9. Fakhouri F, Frmeaux-Bacchi V, Nol LH, Cook HT, et al. C3 glomerulopathy: a new classication. Nat Rev Nephrol. 2010;6: 494-9. 10. Hewins P, Smith RJH, Savage COS. Idiopathic membranoproliferative glomerulonephritis. In: Berl T, Himmelfarb J, Mitch WE, Murphy B, Wilcox CS, Salant DJ, Yu ASL, editors. Therapy in Nephrology and Hypertension. A companion to Brenner & Rectors The Kidney, 3rd ed. Philadelphia:Elsevier Saunders; 2008. p. 249-56. 11. Yamabe H, Johnson RJ, Gretch DR, Fukushi K, et al. Hepatitis C virus infection and membranoproliferative glomerulonephritis in Japan. J Am Soc Nephrol. 1995;6:220-3. 12. Alpers CE, Smith KD. Cryoglobulinemia and renal disease. Curr Opin Nephrol Hypertens. 2008;17:243-9. 13. Hulton SA, Risdon RA, Dillon MJ. Mesangiocapillary glomerulonephritis associated with meningococcal meningitis, C3 nephritic factor and persistently low complement C3 and C5. Pediatr Nephrol. 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. Glomerulonephritis after ventriculo-atrial shunt. QJM. 1995;88:911-8. 16. Adam F, Torun D, Bolat F, Zumrutdal A, et al. Acute renal failure due to mesangial proliferative glomerulonephritis in a pregnant woman with primary Sjgrens syndrome. Clin Rheumatol. 2006; 25:75-9. 17. Weening JJ, DAgati VD, Schwartz MM, Seshan SV, et al. The classication of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int. 2004;65:521-30. 18. Sethi S, Zand L, Leung N, Smith RJH, et al. Membranoproliferative glomerulonephritis secondary to monoclonal gammopathy. Clin J Am Soc Nephrol. 2010;5:770-82. 19. Roccatello D, Fornasieri A, Giachino O, et al. Multicenter study on 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-

22.

23.

24.

25.

26.

27. 28.

29.

30.

31.

32.

33.

34. 35.

36. 37.

38.

39.

40.

348
41. Robert A. Kyle SVR. Monoclonal gammopathy of undetermined signicance. Br J Haematol. 2006;134:573-89. 42. Sethi S, Sukov W, Zhang Y, Fervenza F, et al. Dense deposit disease associated with monoclonal gammopathy of undetermined signicance. Am J Kidney Dis. 2010;56:977-82. 43. Czarnecki PG, Lager DJ, Leung N, Dispenzieri A, et al. Longterm outcome of kidney transplantation in patients with brillary glomerulonephritis or monoclonal gammopathy with brillary deposits. Kidney Int. 2009;75:420-7. 44. Leung N, Lager DJ, Gertz MA, Wilson K, et al. Long-term outcome 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. Recurrent membranoproliferative glomerulonephritis after kidney transplantation. Kidney Int. 2010;77:721-8. 46. Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. 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-

S. Sethi and F.C. Fervenza

branoproliferative glomerulonephritis type II (dense deposit disease). J Med Genet. 2006;43:582-9. Skerka C, Lauer N, Weinberger AAWA, Keilhauer CN, et al. Defective complement control of Factor H (Y402H) and FHL-1 in age-related macular degeneration. Mol Immunol. 2007;44:3398-406. Gale DP, de Jorge EG, Cook HT, et al. Identication of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. The Lancet. 2010;376: 794-801. Sethi S, Fervenza F, Zhang Y, Nasr S, et al. Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway. Clin J Am Soc Nephrol. 2011;6:1009-17. Cosio FG, Gloor JM, Sethi S, Stegall MD. Transplant glomerulopathy. Am J Transplant. 2008;8:492-6. Gloor JM, Sethi S, Stegall MD, Park WD, et al. Transplant glomerulopathy: subclinical incidence and association with alloantibody. Am J Transplant. 2007;7:2124-32. Issa N, Cosio FG, Gloor JM, Sethi S, et al. Transplant glomerulopathy: risk and prognosis related to anti-human leukocyte antigen class II antibody levels. Transplantation. 2008; 86:681-5.

48.

49.

50.

51. 52.

53.