Heymann Nephritis• An experimental rat model of human

membranous nephropathy characterized by complement activation and formation...

Membranoproliferative Glomerulonephritis

Mesangiocapillary Glomerulonephritis

Lobular Glomerulonephritis

Membranoproliferative glomerulonephritis

MPG, also known as mesangiocapillary glomerulonephritis, is a type of glomerulonephritis caused by

• Deposits in mesangium• GBM thickening,• Activating complement &Damaging the glomeruli.

MPGN• MPGN accounts for approximately 4% of

primary renal causes of

nephritic syndrome in children and 7% in adults.

MPGN/ MGN• It should not be confused with

membranous glomerulonephritis, a condition in where the basement membrane is thickened, but the mesangium is not.

MPGN• Because the proliferation is predominantly

in the mesangium but also may involve the capillary loops, a frequently used synonym is

mesangiocapillary glomerulonephritis.

Capillary Wall: Endothelial cells, GBM,

Podocytes

• The glomerular capillary wall is the filtering membrane and consists of the following structures:

• 1.

• 2. GBM• 3. The visceral epithelial cells (podocytes)

with 20-30nm slits, foot processes & slit m.

A thin layer of fenestrated endothelial cells, each fenestrum being about 70 to 100 nm in diameter

Mesangial Cells• The entire glomerular tuft is supported by

mesangial cells lying between the capillaries.

• Basement membrane–like

mesangial matrix forms a meshwork through which the mesangial cells are centered.

Mesangial Cells• These cells, of mesenchymal origin,

are contractile, phagocytic, and capable of proliferation, of laying down both matrix and collagen, and of secreting several biologically active mediators.

Types of Primary MPGN

Primary MPGN• Primary MPGN is divided into two major

types on the basis of distinct ultrastructural, immunofluorescent, and pathologic findings:

• Type I and

• Type II MPGN (dense-deposit disease).

Hypocomplementemia• Type 1–Activation of classical pathway: normal or low

C3, low C1, C4 and low CH50

•Type 2 –Activation of alternate complement pathway:

low C3, normal C1, C4, low CH50

MPGN Type 1• Most common Type

• Discrete immune deposits in the

mesangium and subendothelial space, from circulating immune complexes, this

causes mesangial proliferation and extension into the subendothelial zone.

Circulating Immune Complex Glomerulonephritis

• In this type of nephritis glomerular injury is caused by the trapping of circulating antigen-antibody complexes within glomeruli. The antibodies have no immunological specificity for glomerular constituents, and the complexes localize within the glomeruli because of their physicochemical properties and the hemodynamic factors peculiar to the glomerulus.

Localization of immune complexes in the glomerulus: (1) subepithelial humps, as in acute glomerulonephritis; (2) epimembranous deposits, as in membranous nephropathy and Heymann glomerulonephritis; (3) subendothelial deposits, as in lupus nephritis and membranoproliferative glomerulonephritis; (4) mesangial deposits, as in IgA nephropathy; (5) basement membrane. EN,

endothelium; EP, epithelium; LD, lamina densa; LRE, lamina rara externa; LRI, lamina rara interna; MC, mesangial cell; MM, mesangial matrix.

Pathogenesis (type I)

• The antigens involved in idiopathic MPGN are unknown.

• In many cases they are believed to be

proteins derived from infectious agents such as

hepatitis C and B viruses.

Primary MPGN

Type 2 (Dense Deposit Disease)• 15-35% of total MPGN cases• Characterized by a pathognomonic electron-dense

transformation of GBMs and extensive complement deposition

• Immunofluorescence is positive for C3 but negative for immunoglobulins

Type II MPGN• Antigens presumably behave either as

“planted” antigens after first binding to or becoming trapped within glomerular structures or are contained in preformed immune complexes deposited from the circulation.

Type 2 (Dense Deposit Disease)

• Recurs after renal transplant over 90% of cases• Most have circulating IgG antibody (C3

nephritic factor) that stabilize C3bBb, C3 convertase of alternate pathway, resulted in continuous C3 breakdown. – low C3

• Higher hypocomplementemia and

• worse prognosis

Pathogenesis (type II)• They also have diminished serum levels of

factor B and properdin, components of the alternative complement pathway.

• In the glomeruli, C3 and properdin are deposited, but IgG is not.

• In the alternative complement pathway, C3 is directly cleaved to C3b. The reaction depends on the initial interaction of C3 with such substances as bacterial polysaccharides, endotoxin, and aggregates of IgA in the presence of factors B and D. This leads to the

generation of C3bBb, the alternative pathway C3 convertase.

• This C3 convertase is labile, being degraded by factors I and H, but it can be stabilized by properdin.

The alternative complement pathway in MPGN. Note that C3NeF, an antibody present in the serum of individuals with membranoproliferative glomerulonephritis, acts at the same step as

properdin, serving to stabilize the alternative pathway C3 convertase, thus enhancing C3 activation and consumption, causing hypocomplementemia.

Pathogenesis (type II)• More than 70% of patients with dense-

deposit disease have a circulating antibody

termed C3 nephritic factor (C3NeF), which is an autoantibody that binds to the alternative pathway C3 convertase.

Pathogenesis Type II• Binding of the antibody

stabilizes the convertase, protecting it from enzymatic degradation and thus favoring persistent C3 activation and hypocomplementemia.

Pathogenesis Type II MPGN

• There is also decreased C3 synthesis by the liver, further contributing to the profound hypocomplementemia.

Pathogenesis Type II MPGN

•Precisely how C3NeF is related to glomerular injury and the nature of the dense deposits is unknown.

Pathogenesis Type II MPGN

• C3NeF activity also occurs in some patients with a genetically determined disease, partial lipodystrophy, some of whom develop dense-deposit disease (type II MPGN).

MORPHOLOGYMPGN is characterized histologically by

• GBM thickening• Proliferation of glomerular cells,• Leukocyte infiltration.

Morphology of MPGNBy light microscopy both types of MPGN

are similar. The glomeruli are

Large &

hypercellular.

Hypercellularity Some inflammatory diseases of the glomerulus are

characterized by an increase in the number of cells in the glomerular tufts. This hypercellularity is characterized by one or more combinations of the following:

1. • Cellular proliferation of mesangial or endothelial cells.

2. • Leukocytic infiltration3.• Formation of crescents.

Formation of crescentsThese are accumulations of cells composed of

proliferating parietal epithelial cells and infiltrating leukocytes.

The epithelial cell proliferation that characterizes crescent formation occurs following an immune/inflammatory injury.

Fibrin, which leaks into the urinary space, often through ruptured basement membranes, has been long thought to be the molecule that elicits the crescentic response.

Crescent Formation

• Other molecules that have been implicated in crescent formation and recruitment of leukocytes into crescents include procoagulants such as tissue factor and cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and

interferon-γ.

Morphology of MPGN

• Crescents are present in many cases. The glomeruli have an

“lobular” appearance

due to the proliferating mesangial cells and increased mesangial matrix.

Morphology of MPGN

•The GBM is thickened.

• The glomerular capillary wall often shows

a “double-contour” or

“tram-track” appearance.

Morphology of MPGNWithin the duplicated basement membranes

there is inclusion or interposition of cellular elements, appearance of

“split” basement membranes.

Morphology Type ITypes I and II MPGN differ in their ultrastructural

and immunofluorescent features.

EM: Type I MPGN is characterized by the presence of

discrete subendothelial electron-dense deposits.

Morphology type I• By immunofluorescence,

C3 is deposited in a granular pattern,

and IgG and early complement components

(C1q and C4) are often also present, suggesting an

immune complex pathogenesis.

Schematic representation of a glomerular lobe.

Light Microscopy

Electron Micrograph

Immunofluorescence

Morphology of MPGN II

• In dense-deposit disease (type II MPGN), a relatively rare entity, the lamina densa of the

GBM is transformed into an irregular, ribbon-like, extremely electron-dense structure due to the deposition of dense material of unknown composition in the GBM proper.

Morphology of MPGN II

• C3 is present in irregular granular or linear foci in the basement membranes on either side but not within the dense deposits.

• C3 is also present in the mesangium in characteristic circular aggregates (mesangial rings).

• IgG is usually absent, as are the early-acting complement components (C1q and C4).

Electron micrography

A, Membranoproliferative glomerulonephritis, type I. Note discrete electron-dense deposits (arrows) incorporated into the glomerular capillary wall between duplicated (split) basement membranes (double arrows), and in mesangial regions

(M); CL, capillary lumen. B, Dense-deposit disease (type II membranoproliferative glomerulonephritis). There are markedly dense homogeneous deposits within the basement membrane proper. CL, capillary lumen. In both, mesangial

interposition gives the appearance of split basement membranes when viewed in the light microscope. C, Schematic representation of patterns in the two types of membranoproliferative GN. In type I there are subendothelial deposits; type II is characterized by intramembranous dense deposits (dense-deposit disease). In both, mesangial interposition

gives the appearance of split basement membranes when viewed in the light microscope.

Type 3• Similar to type 1 but subepithelial

deposits are prominent and complex disruption of the GBM

• Inherited form of type 3 linked to chromosome 1q32

Etiology• Primary (idiopathic) vs. Secondary• Autoimmune disorders – SLE, Sjogren’s, Rheumatoid arthiritis, hereditary

complement deficient state

• Infections – chronic infections rather than acute; Hep B, Hep C, SBE, ventriculoatrial shunt infection, chronic visceral abscess, HIV, schistosomiasis, malaria, leprosy.

• Thrombotic microangiopathies – transplant glomerulopathy, antiphospholipid antibody syndrome, TTP/HUS, scleroderma

• Others – lipodystrophy, CLL, melanoma, alpha-1-antitrypsin deficiency, non-Hodgkin’s, renal cell carcinoma

• Association with HIV in the absence of HCV not well known.

Severity of disease• Renal function

• Urine protein excretion

• Histologic features such as necrosis, sclerosis, tubular and vascular fibrosis are late in course with less reversibility

• Kidney size (<9cm) and echogenic on US – no benefit from disease-specific therapy

Clinical Features. Most patients present in adolescence or as young

adults with nephrotic syndrome and a nephritic component manifested by hematuria or, more insidiously, as mild proteinuria.

Clinical features

Few remissions occur spontaneously in either type, and the disease follows a slowly progressive but unremitting course.

Clinical features

Some patients develop numerous crescents and a clinical picture of RPGN.

About 50% develop chronic renal failure within 10 years.

Clinical featuresTreatments with steroids, immunosuppressive

agents, and antiplatelet drugs have not been proved to be materially effective.

Clinical features

• There is a high incidence of recurrence in transplant recipients, particularly in dense-deposit disease; dense deposits may recur in 90% of such patients, although renal failure in the allograft is much less common.

Secondary MPGN Secondary MPGN (invariably type I) is more common

in adults and arises in the following settings:

• Chronic immune complex disorders, such as SLE; hepatitis B infection; hepatitis C infection, usually with cryoglobulinemia; endocarditis; infected ventriculoatrial shunts; chronic visceral abscesses; HIV infection; and schistosomiasis.

Secondary MPGN

• α1-Antitrypsin deficiency

• Malignant diseases (chronic lymphocytic leukemia and lymphoma)

• Hereditary deficiencies of complement regulatory proteins

Hepatitis C induced Type 1MPGN

• MPGN has been regarded as idiopathic for a long time until found out many also have chronic Hep C.

• Strongly associated with cryoglobulinemia but mechanism is not well known – intraluminal precipitates of immune complexes involving the cryoglobulins.

Hepatitis C induced Type 1MPGN

• Incidence varies with location – uncommon in France and South Africa, common in Japan

• Commonly presents after 10-15yrs of chronic Hep C.

• Laboratory features : HCV antibody, HCV RNA by PCR, high concentration of cryoglobulins, positive RF and low complement.

Treatment• Treatment goals include reduction of

symptoms, prevention of complications, and slowed progression of the disorder. • Treating secondary causes.

Treatment• Idiopathic MPGN - spontaneous

improvement in <10%, 25-40% maintain renal function, 50-60% to ESRD in 10years

• Corticosteroid – more commonly used in children

Treatment

• Antiplatelet agents – uncertain but showed some benefit with ASA and dipyridamole (reduced the incidence of progression to ESRD – 14 vs. 47% in 3-5 yrs)

• Immunosuppressive drugs – limited data

Treatment

• Dietary adjustments may include restrictions on sodium, fluids, protein, or other restrictions as appropriate to control high blood pressure, swelling, and accumulation of waste products in the bloodstream.