Membranoproliferative Glomerulonephritis

Agnes B. Fogo

Introduction/Clinical Setting

Membranoproliferative glomerulonephritis (MPGN) refers to a pattern of injury characterized by diffuse mesangial expansion due to endocapillary proliferation and increased mesangial matrix, and thickened capillary walls, often with a split "tram-track" appearance (1,2). The immune complexes may be undefined in terms of the inciting antigen ("idiopathic") or secondary to chronic infections (3). Of note, basement membrane splitting may be seen in other non-immune complex injuries, such as the late phase of thrombotic microangiopathy (3). Although light microscopy may appear similar to MPGN, immunofluorescence findings and electron microscopy readily allow recognition of the immune complexes in MPGN. We and others prefer to use the term membranoproliferative glomerulonephritis only for immune complex glomerulonephritides with this pattern (1). Membranoproliferative glomerulonephritis type I typically presents as combined nephritic/nephrotic syndrome with hypocomplementemia. Patients typically have progressive renal disease, with about 50% renal survival at 10 years in children, and similar rates of progression in adults. Idiopathic MPGN is more common in children and young adults, whereas MPGN-type lesions are more commonly secondary to chronic infections in adults. New insights into the role of complement regulation in renal injury are adding to our understanding of the etiology of injury in cases previously classified as idiopathic.

Pathologic Findings Light Microscopy

Membranoproliferative glomerulonephritis has been divided into three types. Type I characteristically has subendothelial deposits, resulting in a thickened capillary wall and a double contour of the glomerular basement membrane (GBM) by silver stains, and endocapillary proliferation (1,4).

Membranoproliferative Glomerulonephritis
Figure 3.1. Lobular appearance due to diffuse, global endocapillary proliferation of all glomeruli in membranoproliferative glomerulonephritis (MPGN) type I [periodic acid-Schiff (PAS)].

This appearance results from so-called circumferential mesangial interposition, whereby mesangial cells, infiltrating mononuclear cells, or even portions of endothelial cells interpose themselves between the endothe-lium and the basement membrane, with new, inner basement membrane being laid down (5). A circumferential, or partial, double contour basement membrane results. Of note, in non-immune complex diseases with splitting seen by light microscopy (e.g., transplant glomerulopathy, chronic injury after hemolytic uremic syndrome), electron microscopy shows that the double contour results from widening of the GBM due to increased lucency of the lamina rara interna with new basement membrane formed underneath the endothelium. In MPGN type I, the glomeruli show endo-capillary proliferation with increased mesangial cellularity and matrix, and lobular simplification (Figs. 3.1 to 3.3). The term mesangiocapillary glo-

Membrane Basale
Figure 3.2. Diffuse, global endocapillary proliferation with extensive glomerular basement membrane (GBM) splitting in MPGN type I (Jones silver stain).
Basement Membrane Splitting
Figure 3.3. Diffuse, global endocapillary proliferation with GBM splitting and visible large subendothelial deposits in MPGN type I (Jones silver stain).

merulonephritis has also been used for MPGN type I. Increased mononuclear cells and occasional neutrophils may be present. The proliferation is typically uniform and diffuse in idiopathic MPGN, contrasting the irregular involvement most commonly seen in proliferative lupus nephritis (Fig. 3.1). In secondary forms of MPGN, the injury may be more irregular. Crescents may occur in both idiopathic and secondary forms. Deposits do not involve extraglomerular sites. Lesions progress with less cellularity and more pronounced matrix accumulation and sclerosis over time (6). Tubular and vascular fibrosis and sclerosis proportional to glomerular scarring are seen late in the course.

Dense deposit disease (DDD), also called MPGN type II, is a separate disease entity from MPGN type I. Due to its similar light microscopic appearance, it conventionally has been classified with MPGN (7). It is much rarer than type I, accounting for 15% to 35% of total MPGN cases. By light microscopy, endocapillary proliferation is present. The basement membranes are thickened and highly refractile and eosinophilic, with involved areas with strings of deposits looking like a string of sausages. The deposits are periodic acid-Schiff (PAS) positive and stain brown with silver stain. Thickening also affects tubular basement membranes and Bowman's capsule. Crescents may be present.

Membranoproliferative glomerulonephritis type III shows, in addition to the subendothelial and mesangial deposits, numerous subepithelial deposits. It may not, however, represent an entity separate from MPGN type I (8,9). Although C3 nephritic factor is rarely found in these patients, clinical distinction of this morphology has not been apparent.

Immunofluorescence Microscopy

The immunofluorescence findings are variable in MPGN type I. Typically, immunoglobulin G (IgG) and IgM and C3 are present in an irregular capil-

Figure 3.4. Coarsely granular capillary loop and mesangial deposits in MPGN [anti-immunoglobulin G (IgG) antibody immunofluorescence].

lary and mesangial distribution (Fig. 3.4). Immunoglobulin A (IgA) is present in only a small proportion of cases. Of note, C3 staining may be dominant, and staining for immunoglobulin may even be lost, especially in secondary MPGN.

In DDD, C3 staining outlines the capillary wall, and may be smooth, granular, or discontinuous. Mesangial bright granular staining can be present. Immunoglobulin is usually not detected, indicating the dense deposits are not classic antigen-antibody immune complexes. However, segmental IgM or less often IgG and very rarely IgA have been reported (10).

Electron Microscopy

By electron microscopy, MPGN type I shows numerous dense deposits in subendothelial and mesangial areas (Fig. 3.5). Vague wormy or microtu-

Immune Electron Microscopy
Figure 3.5. Subendothelial immune complex deposits in MPGN type I (electron microscopy).
Figure 3.6. Intracapillary deposits with vague, short fibrillary substruture, in MPGN caused by hepatitis C-associated cryoglobulin (electron microscopy).

bular substructure suggests a possible cryoglobulin component (Fig. 3.6). So-called mesangial interposition is detected (Fig. 3.7), which refers to the interposition of cytoplasmic processes of mononuclear cells between the endothelial cell and the basement membrane. The precise origin of the interposing cells has not been directly proven, and they may in fact be derived from mononuclear inflammatory cells. Reduplication of new basement material is present immediately under the swollen endothelial cells, resulting in the splitting visualized by light microscopy by silver stains (1,4).

The lamina densa of the basement membrane in DDD shows a very dense transformation without discrete immune complex-type deposits

Subendothelial Deposits
Figure 3.7. Subendothelial deposits with underlying interposed cell (so-called mesangial interposition) and underlying new GBM formation, resulting in split appearance by light microscopy in MPGN (electron microscopy).
Figure 3.8. Dense transformation of the GBM in dense deposit disease (electron microscopy).

(Fig. 3.8) (7,11). Similar dense material is often found in the mesangial areas in addition to increased matrix. Increased mesangial cellularity and/ or mesangial interposition are far less common than in type I MPGN. Epithelial cells show varying degrees of reactive changes, from vacuolization, to microvillous transformation, to foot process effacement. Tubular basement membranes and Bowman's capsule may show similar densities. The precise nature of the dense material is not established. However, studies support the idea that these densities represent a biochemical modification of the glycoprotein components of the normal basement membrane.

Etiology/Pathogenesis

The MPGN lesions have been recognized to occur secondary to a number of chronic infectious processes, including hepatitis B, hepatitis C, syphilis, subacute bacterial endocarditis, etc. Membranoproliferative glomerulone-phritis may rarely occur due to inherited deficiency of complement, or partial lipodystrophy. If a chronic bacterial infection is causing MPGN-type lesions, hump-type subepithelial deposits may be present (see Chapter 5).

Generally, morphologic features do not allow precise classification of the underlying agent in most cases of type I MPGN. However, a large number (~25% in the United Sates) of previously idiopathic MPGN cases in adults have been associated with hepatitis C infection (12). This association was not seen in a U.S. series of children with MPGN. Morphologic features suggestive of hepatitis C with cryoglogulin as an underlying cause include vague substructure of deposits, with short, curved, vaguely fibrillar deposits (Fig. 3.6) (suggestive of mixed cryoglobulinemia), or rarely microtubu-lar substructure, strongly PAS-positive cryo-"plugs" in capillary lumina (Fig. 3.9), vasculitis, predominant IgM deposits, sometimes with clonality (13). Cryoglobulinemia is commonly associated with hepatitis C, an RNA virus (14,15). Approximately 150,000 cases of hepatitis C infection occur per year in the United States. Of these, approximately half have liver disease, with 15,000 developing chronic active hepatitis and/or cirrhosis. The prevalence of hepatitis C infection is approximately 0.6% in the United States, reaching up to 6% in Africa. In one large series of hepatitis C-positive cases affecting the kidney, 40 patients with an average age of 46 years were studied. The most common risk factors for infection in this series were intravenous drug abuse, and blood transfusion. The mixed type 2 cryoglobulinemia associated with various infections is postulated to be due to the production of rheumatoid factor in response to complexes of IgG bound to foreign antigens (16). Hepatitis C virus RNA precipitated with cryoglobulin in serum samples from patients with type 2 mixed cryo-globulinemia, supporting a role for the virus as an antigen in the cryo-globulin (16). Cryoglobulinemia may also manifest as a more acute glomerulonephritis, and may even show strongly PAS-positive cryo-plugs (hyaline thrombi) visualized in capillary lumina (Fig. 3.9). Deposits of

Figure 3.9. Global endocapillary proliferation, splitting of GBM and brightly PAS-positive so-called cryo-plugs in capillary lumina, characteristic of MPGN due to cryoglobulins (PAS).

cryoglobulin typically show vague, short, fibrillary substruture by electron microscopy (Fig. 3.6). There may also be vasculitis involving medium-sized arteries in cryoglobulinemic glomerulonephritis.

In contrast, DDD has a distinct pathogenesis related to IgG autoantibodies (C3 nephritic factor, C3NeF) directed at C3 convertase, resulting in alternate pathway complement activation. C3NeF stabilizes the C3 convertase C3bBb, resulting in alternate pathway-mediated C3 breakdown and decreased C3. Early components of the classic pathway, that is, C1q and C4, usually show normal serum levels. Sometimes DDD occurs in association with partial lipodystrophy, a condition with loss of adipose tissue, decreased complement, and the presence of C3NeF (7,17). Further, a porcine model of factor H deficiency has similarities to DDD (18). Factor H inactivates factor C3bBb. These associations have suggested that abnormal complement regulation predisposes to DDD. However, clinical measures of complement, C3NeF, or presence of partial lipodystrophy did not predict clinical outcome among patients with DDD, and some patients with MPGN type 1 also have C3NeF. Some patients with partial lipodystrophy and C3NeF do not have DDD, further indication that complement abnormalities alone are insufficient to produce the disease.

Clinicopathologic Correlations

Type I MPGN has an inexorable downhill course clinically (1,17,19). Patients present with proteinuria, which reaches nephrotic levels in two thirds. Renal disease associated with hepatitis C and cryoglobulin most often is manifest as type I MPGN, although membranous glomerulone-phritis has been described. Patients with cryoglobulins often have systemic disease in addition to renal involvement (20). Necrotizing arteritis may also occur secondary to hepatitis C infection (21-23). In these patients with renal disease and hepatitis C infection, purpura is frequently present. Sixteen percent showed signs of liver disease. Tests for cryoglobulins were positive at some point of the disease course in 80% of patients. Most patients showed decreased complement (90%). Demonstration of hepatitis C in kidney tissue has not been documented directly within deposits. However, hepatitis C virus-like particles have been identified within the dense deposits, and hepatitis C virus has been isolated from renal tissue (12).

Treatment so far has offered limited success. Type I MPGN has recurred in up to 30% of transplants in some series (17). However, the disease may have a more benign clinical course when it recurs. Interferon-a therapy decreases symptoms of renal involvement in hepatitis C-associated MPGN, but relapses are prompt as soon as therapy is discontinued (12). Dense deposit disease has very frequent, near 100% morphologic recurrence in the transplant, but renal failure does not usually result (17,24).

References

1. Habib R, Kleinknecht C, Gubler MC, Levy M. Idopathic membranoprolifera-tive glomerulonephritis in children: report of 105 cases. Clin Nephrol 1:194— 214, 1973.

2. Strife CF, McEnery PT, McAdams A J, West CD. Membranoproliferative glomerulonephritis with disruption of the glomerular basement membrane. Clin Nephrol 7:65-72, 1977.

3. Rennke HG. Nephrology forum: secondary membranoproliferative glomeru-lonephritis. Kidney Int 47:643-656, 1995.

4. Jones DB. Glomerulonephritis. Am J Pathol 29:33-51, 1953.

5. Katz SM. Reduplication of the glomerular basement membrane: a study of 110 cases. Arch Pathol Lab Med 105:67-70, 1981.

6. Taguchi T, Bohle A. Evaluation of change with time of glomerular morphology in membranoproliferative glomerulonephritis: a serial biopsy study of 33 cases. Clin Nephrol 31:297-306, 1989.

7. Habib R, Gubler MC, Loirat C, Maiz HB, Levy M. Dense deposit disease: a variant of membranoproliferative glomerulonephritis. Kidney Int 7:204-215, 1975.

8. Anders D, Agricola B, Sippel M, Theones W. Basement membrane changes in membranoproliferative glomerulonephritis. II. Characterization of a third type by silver impregnation of ultra thin sections: Virchows Arch [Pathol Anat] 376:1-19, 1977.

9. Strife CF, Jackson EC, McAdams AJ. Type III membranoproliferative glomerulonephritis: long-term clinical and morphological evaluation. Clin Nephrol 21:323-334, 1984.

10. Belgiojoso GB, Tarantino A, Bazzi C, Colasanti G, Guerra L, Durante A. Immunofluorescence patterns in chronic membranoproliferative glomerulonephritis (MPGN). Clin Nephrol 6:303-310, 1976.

11. Berger J, Galle P. Dépots denses au sein des membranes basales du rein: étude en microscopies optique et électronique. Presse Med 71:2351-2354, 1963.

12. Johnson RJ, Gretch DR, Yamabe H, et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 328: 465-470, 1993.

13. Feiner H, Gallo G. Ultrastructure in glomerulonephritis associated with cryoglobulinemia. A report of six cases and review of the literature. Am J Pathol 88:145-155, 1977.

14. Misiani R, Bellavita P, Fenili D, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 117:573-577, 1992.

15. Pascual M, Perrin L, Giostra E, Schifferli JA. Hepatitis C virus in patients with cryoglobulinemia type II. J Infect Dis 162:569-570, 1990.

16. Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 327:1490-1495, 1992.

17. Cameron JS, Turner DR, Heaton J, et al. Idiopathic mesangiocapillary glo-merulonephritis. Comparison of types I and II in children and adults and long-term prognosis. Am J Med 74:175-192, 1983.

18. Hegasy GA, Manuelian T, Hogasen K, Jansen JH, Zipfel PF. The molecular basis for hereditary porcine membranoproliferative glomerulonephritis type

II: point mutations in the factor H coding sequence block protein secretion. Am J Pathol 161:2027-2034, 2002.

19. Droz D, Noel LH, Barbonel C, Grünfeld JP. Long-term evolution of membra-noproliferative glomerulonephritis in adults: spontaneous clinical remission in 13 cases with proven regression of glomerular lesions in 5 cases. Nephrologie 3:6-11, 1982.

20. Ferri C, Greco F, Longombardo G, et al. Association between hepatitis C virus and mixed cryoglobulinemia. Clin Exp Rheumatol 9:621-624, 1992.

21. Druet P, Letonturier P, Contet A, Mandet C. Cryoglobulinaemia in human renal diseases. A study of seventy-six cases. Clin Exp Immunol 15:483-496, 1973.

22. Perez GO, Pardo V, Fletcher MA. Renal involvement in essential mixed cryoglobulinemia. Am J Kidney Dis 10:276-280, 1987.

23. Tarantino A, De Vecchi A, Montagnino G, et al. Renal disease in essential mixed cryoglobulinaemia. Q J Med 50:1-30, 1981.

24. Andresdottir MB, Assmann KJ, Hoitsma AJ, et al. Renal transplantation in patients with dense deposit disease: morphological characteristics of recurrent disease and clinical outcome. Nephrol Dial Transplant 14:1723-1731, 1999.

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